piperidines and Nerve-Degeneration

Dopamine depletion is one of the most important features of Parkinson's Disease (PD). However, insufficient response to dopaminergic replacement therapy suggests the involvement of other neurotransmitter systems in the pathophysiology of PD. Cholinergic degeneration contributes to gait impairments, cognitive impairment, psychosis, and REM-sleep disturbances, among other symptoms. Areas covered: In this review, we explore the idea that enhancing cholinergic tone by pharmacological or neurosurgical procedures could be a first-line therapeutic strategy for the treatment of symptoms derived from cholinergic degeneration in PD. Expert opinion: Rivastigmine, a drug that increases cholinergic tone by inhibiting the enzyme cholinesterase, is effective for dementia, whereas the use of Donepezil is still in the realm of investigation. Interesting results suggest the efficacy of these drugs in the treatment of gait dysfunction. Evidence on the clinical effects of these drugs for psychosis and REM-sleep disturbances is still weak. Stimulation of the pedunculo-pontine tegmental nuclei (which provide cholinergic innervation to the brain stem and subcortical nuclei) has also been used with some success for the treatment of gait dysfunction. Anticholinergic drugs should be used with caution in PD, as they may aggravate cholinergic symptoms. Notwithstanding, in some patients they might help control parkinsonian motor symptoms.

Topics: Animals; Cholinergic Agents; Cholinergic Neurons; Clinical Trials as Topic; Cognition Disorders; Dementia; Donepezil; Gait; Humans; Indans; Nerve Degeneration; Parkinson Disease; Piperidines; Psychotic Disorders

Of the estimated 5.3 million people with Alzheimer's disease in the United States, more than half would be classified as having moderate or severe disease. Alzheimer's disease is a progressive disorder with the moderate to severe stages generally characterized by significant cognitive, functional, and behavioral dysfunction. Unsurprisingly, these advanced stages are often the most challenging for both patients and their caregivers/families. Symptomatic treatments for moderate to severe Alzheimer's disease are approved in the United States and include the acetylcholinesterase inhibitor donepezil and the glutamate receptor antagonist memantine. Progressive symptomatic decline is nevertheless inevitable even with the available therapies, and therefore additional treatment options are urgently needed for this segment of the Alzheimer's disease population. An immediate-release formulation of donepezil has been available at an approved dose of 5-10 mg/d for the past decade. Recently, the United States Food and Drug Administration approved a higher-dose (23 mg/d) donepezil formulation, which provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) versus the immediate-release formulation (3 hours), and higher daily concentrations. Herein, we review (1) the scientific data on the importance of cholinergic deficits in Alzheimer's disease treatment strategies, (2) the rationale for the use of higher-dose acetylcholinesterase inhibitors in patients with advanced disease, and (3) recent clinical evidence supporting the use of higher-dose donepezil in patients with moderate to severe Alzheimer's disease.

Topics: Acetylcholine; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Clinical Trials as Topic; Delayed-Action Preparations; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Nerve Degeneration; Piperidines; Severity of Illness Index

An increasing number of studies suggest that current pharmacotherapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The oldest hypothesis explain the cause of the AD is the "cholinergic hypothesis", which states, that AD begins as a deficiency in the production of acetylcholine (ACh). Interactions between the cholinergic and serotoninergic systems are believed to play a role in the mechanism underlying AD. The activation of NMDA receptors and increase in intracellular Ca(++) concentration play key role in the development of neurodegenerative processes. Potassium channels may also be involved in several other steps within the cascade that leads to neurodegeneration. In the development of AD a great role play an imbalance between anabolism and catabolism causes an accumulation of amyloid beta-peptide (Abeta), which is a proposed trigger of the onset of AD. There are various therapeutic strategies in current pharmacotherapy of AD. Major group is inhibitors of acetylcholinesterase--donepezil, galantamine, physostigmine. The new effective treatments of AD are NMDA glutamate receptor antagonist-memantine and potassium channel openers such as retigabine. Experimental study suggest, that neprilisin, a rate-limiting peptidase, decreases neurodegeneration.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Middle Aged; Nerve Degeneration; Piperidines

Topics: Acetylcholine; Amygdala; Animals; Brain; Cholinesterase Inhibitors; Convulsants; Electric Stimulation; Epilepsy; Kainic Acid; Lithium; Nerve Degeneration; Neural Pathways; Neurons; Neurotransmitter Agents; Piperidines; Rats; Somatosensory Cortex; Synaptic Transmission

Topics: Animals; Aziridines; Choline; Colchicine; Folic Acid; Glutamates; Glutamic Acid; Ibotenic Acid; Kainic Acid; Lectins; Mitogens; Mustard Compounds; Nerve Degeneration; Nervous System; Neurons; Piperidines; Pyrrolidonecarboxylic Acid; Quinolinic Acid; Quinolinic Acids

Thirty-seven non-IDDM patients at an early stage of polyneuropathy, defined as the presence of symptoms for less than two years, as well as an abnormal perception threshold and/or abnormal thermal discrimination threshold, were treated with sabeluzole, a new antihypoxic drug, or placebo for 1 year in a double-blind, placebo-controlled study. They were examined neurophysiologically every 3 months, when motor (tibial, ulnar) nerve and sensory (sural, ulnar) nerve conduction velocities, H-reflex of the soleus muscle, SF-EMG of the anterior tibial muscle, static and dynamic pupillometry were measured. Statistical analysis did not show significant differences in nerve function between the sabeluzole group and the placebo group. There were also no significant changes within each group over the 1-year period. The results of the present study show no beneficial effect of sabeluzole on peripheral nerve function in patients at an early stage of diabetic polyneuropathy.

Topics: Adult; Aged; Autonomic Nervous System Diseases; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Electromyography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nerve Degeneration; Neurologic Examination; Peripheral Nerves; Piperidines; Sensory Thresholds; Synaptic Transmission; Thiazoles

The activation of the G-protein coupled receptor CXCR4 by its ligand CXCL12α is involved in a large variety of physiological and pathological processes, including the growth of B cells precursors and of motor axons, autoimmune diseases, stem cell migration, inflammation, and several neurodegenerative conditions. Recently, we demonstrated that CXCL12α potently stimulates the functional recovery of damaged neuromuscular junctions via interaction with CXCR4. This result prompted us to test the neuroregeneration activity of small molecules acting as CXCR4 agonists, endowed with better pharmacokinetics with respect to the natural ligand. We focused on NUCC-390, recently shown to activate CXCR4 in a cellular system. We designed a novel and convenient chemical synthesis of NUCC-390, which is reported here. NUCC-390 was tested for its capability to induce the regeneration of motor axon terminals completely degenerated by the presynaptic neurotoxin α-Latrotoxin. NUCC-390 was found to strongly promote the functional recovery of the neuromuscular junction, as assayed by electrophysiology and imaging. This action is CXCR4 dependent, as it is completely prevented by AMD3100, a well-characterized CXCR4 antagonist. These data make NUCC-390 a strong candidate to be tested in human therapy to promote nerve recovery of function after different forms of neurodegeneration.

Topics: Animals; Benzylamines; Cyclams; Heterocyclic Compounds; Indazoles; Mice; Mice, Inbred Strains; Motor Neurons; Nerve Degeneration; Nerve Regeneration; Neuromuscular Junction; Piperidines; Presynaptic Terminals; Primary Cell Culture; Pyridines; Rats; Receptors, CXCR4; Spider Venoms

Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer's disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear. The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here, we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD. We observed that expression of APP and β-secretase as well as production of total Aβ and Aβ42 were significantly reduced in APP transgenic mice lacking CB2R (TG-CB2-KO) treated with JZL184, a selective and potent inhibitor for MAGL. Inactivation of MAGL also alleviated neuroinflammation and neurodegeneration in TG-CB2-KO mice. Importantly, TG-CB2-KO mice treated with JZL184 still exhibited improvements in spatial learning and memory. In addition, MAGL inhibition prevented deterioration in expression of important synaptic proteins in TG-CB2-KO mice. Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals.

Topics: Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Astrocytes; Benzodioxoles; Brain; Cognition; Disease Models, Animal; Mice; Mice, Transgenic; Monoacylglycerol Lipases; Nerve Degeneration; Piperidines; Receptor, Cannabinoid, CB2; Spatial Learning

Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17.. In this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression.. Addition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress.. Our study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17.

Topics: Alkaloids; Animals; Benzodioxoles; Brain; Endoplasmic Reticulum Stress; Mice; Mice, Transgenic; Nerve Degeneration; Nerve Growth Factors; Neuroprotective Agents; Piperidines; Polyunsaturated Alkamides; TATA-Box Binding Protein

Flavonoids are bioactive compounds that are known to be neuroprotective against glutamate-mediated excitotoxicity, one of the major causes of neurodegeneration. The mechanisms underlying these effects are unresolved, but recent evidence indicates flavonoids may modulate estrogen signaling, which can delay the onset and ameliorate the severity of neurodegenerative disorders. Furthermore, the roles played by glial cells in the neuroprotective effects of flavonoids are poorly understood. The aim of this study was to investigate the effects of the flavonoid agathisflavone (FAB) in primary neuron-glial co-cultures from postnatal rat cerebral cortex. Compared to controls, treatment with FAB significantly increased the number of neuronal progenitors and mature neurons, without increasing astrocytes or microglia. These pro-neuronal effects of FAB were suppressed by antagonists of estrogen receptors (ERα and ERβ). In addition, treatment with FAB significantly reduced cell death induced by glutamate and this was associated with reduced expression levels of pro-inflammatory (M1) microglial cytokines, including TNFα, IL1β and IL6, which are associated with neurotoxicity, and increased expression of IL10 and Arginase 1, which are associated with anti-inflammatory (M2) neuroprotective microglia. We also observed that FAB increased neuroprotective trophic factors, such as BDNF, NGF, NT4 and GDNF. The neuroprotective effects of FAB were also associated with increased expression of glutamate regulatory proteins in astrocytes, namely glutamine synthetase (GS) and Excitatory Amino Acid Transporter 1 (EAAT1). These findings indicate that FAB acting via estrogen signaling stimulates production of neurons in vitro and enhances the neuroprotective properties of microglia and astrocytes to significantly ameliorate glutamate-mediated neurotoxicity.

Topics: Animals; Astrocytes; Biflavonoids; Cell Death; Cerebral Cortex; Coculture Techniques; Cytokines; Excitatory Amino Acid Transporter 1; Fabaceae; Glutamate-Ammonia Ligase; Glutamic Acid; Microglia; Nerve Degeneration; Nerve Growth Factors; Neurogenesis; Neurons; Neuroprotective Agents; Piperidines; Primary Cell Culture; Pyrazoles; Pyrimidines; Rats

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD

Topics: Acrylamides; Animals; Antineoplastic Agents, Phytogenic; Drug Combinations; Francisella tularensis; Ganglia, Spinal; NAD; Nerve Degeneration; Neurons; Niacinamide; Nicotinamide Mononucleotide; Nicotinamide Phosphoribosyltransferase; Piperidines; Pyridinium Compounds; Vincristine

Dangui-Jakyak-San (DJ) is a traditional Korean medicinal polyherb, prescribed typically in patients with insufficient blood supply in Eastern Asia. The DJ also has been reported to have neuroprotective effects in vitro and in vivo studies.. The therapeutic potential of DJ was examined in stroke rat model, in comparison with donepezil, a reversible acetylcholinesterase inhibitor.. Ischemic stroke rat model was induced by surgery of permanent occlusion of middle cerebral artery (pMCAO). The model was orally administered with distilled water (pMCAO control), donepezil at 10mg/kg (Donepezil) and DJ at 200, 100 and 50mg/kg (DJ 200, DJ 100 and DJ 50, respectively). Sham had the same surgery excepting for the pMCAO, and it was administered with distilled water (sham control).. After the administration for 28 days, the groups of DJ exhibited dose-dependent reduction in infarct/defect volumes with improvement in sensorimotor and cognitive motor function, comparing to pMCAO control. The DJ treatments seemed to enhance antiapoptotic and antioxidant effects; increases in antiapoptotic expressions (STAT3 and Pim-1) and decreases in lipid peroxidation (MDA) together with increases in contents of endogenous antioxidant (GSH) and activities of antioxidant enzymes (catalase and SOD). The histopathological analyses revealed significant reduction in neuronal apoptosis (caspase-3 and PARP) and neuronal degradation with atrophy and degeneration, in the DJ treatments. Furthermore, the oxidative stresses (nitrotyrosine as an iNOS factor and 4-HNE as a marker of lipid peroxidation) were observed mild. Although the similar neuroprotective effects were observed, the body weight loss was scarcely alleviated in Donepezil comparing to pMCAO control.. These suggest that DJ ameliorate the neurological dysfunction of cerebral ischemia through augmentation of antioxidant defense system and up-regulation of STAT3 and Pim-1.

Topics: Animals; Antioxidants; Apoptosis; Behavior, Animal; Biomarkers; Caspase 3; Cerebral Cortex; Cholinesterase Inhibitors; Cognition; Disease Models, Animal; Donepezil; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Indans; Infarction, Middle Cerebral Artery; Lipid Peroxidation; Male; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Piperidines; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-pim-1; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Time Factors

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal; Auditory Perception; CA1 Region, Hippocampal; Choline O-Acetyltransferase; Cholinergic Neurons; Disease Models, Animal; Donepezil; Electrodes, Implanted; Evoked Potentials, Auditory; Indans; Male; Nerve Degeneration; Neuroprotective Agents; Neuropsychological Tests; Piperidines; Psychomotor Performance; Rats, Sprague-Dawley; Ribosome Inactivating Proteins, Type 1; Saporins

The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response and controls inflammation employing acetylcholine as the key endogenous mediator. In this study, we investigated the effects of the cholinergic agonists, physostigmine and donepezil, on neurodegeneration, inflammation and oxidative stress during oxygen toxicity in the developing rat brain. The aim of this study was to investigate the level of neurodegeneration, expression of proinflammatory cytokines, glutathione and lipid peroxidation after hyperoxia and treatment with the acetylcholinesterase (AChE) inhibitors, physostigmine and donepezil in the brain of neonatal rats. Six-day-old Wistar rats were exposed to 80% oxygen for 12-24 h and received 100 μg/kg physostigmine or 200 μg/kg donepezil intraperitoneally. Sex-matched littermates kept in room air and injected with normal saline, physostigmine or donepezil served as controls. Treatment with both inhibitors significantly reduced hyperoxia-triggered activity of AChE, neural cell death and the upregulation of the proinflammatory cytokines IL-1β and TNF-α in the immature rat brain on the mRNA and protein level. In parallel, hyperoxia-induced oxidative stress was reduced by concomitant physostigmine and donepezil administration, as shown by an increased reduced/oxidized glutathione ratio and attenuated malondialdehyde levels, as a sign of lipid peroxidation. Our results suggest that a single treatment with AChE inhibitors at the beginning of hyperoxia attenuated the detrimental effects of oxygen toxicity in the developing brain and may pave the way for AChE inhibitors, which are currently used for the treatment of Alzheimer's disease, as potential candidates for adjunctive neuroprotective therapies to the immature brain.

Topics: Animals; Animals, Newborn; Blotting, Western; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Female; Hyperoxia; Immunohistochemistry; Indans; Male; Nerve Degeneration; Oxidative Stress; Oxygen; Physostigmine; Piperidines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction

The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable with the third trimester in human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. In this study, we investigated the potential role of endocannabinoids and the cannabinoid receptor type 1 (CB1R) in neonatal neurodegeneration and adult synaptic dysfunctions in mice exposed to ethanol at P7. Ethanol treatment at P7, which induces neurodegeneration, increased anandamide (AEA) but not 2-arachidonylglycerol biosynthesis and CB1R protein expression in the hippocampus and cortex, two brain areas that are important for memory formation and storage, respectively. N-Arachidonoyl phosphatidylethanolamine-phospholipase D (NAPE-PLD), glycerophosphodiesterase (GDE1), and CB1R protein expression were enhanced by transcriptional activation of the genes encoding NAPE-PLD, GDE1, and CB1R proteins, respectively. In addition, ethanol inhibited ERK1/2 and AKT phosphorylation. The blockade of CB1Rs before ethanol treatment at P7 relieved ERK1/2 but not AKT phosphorylation and prevented neurodegeneration. CB1R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2 phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Brain; Cannabinoid Receptor Antagonists; Endocannabinoids; Ethanol; Female; Gene Expression Regulation, Developmental; Glycerides; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Degeneration; Nerve Tissue Proteins; Neuronal Plasticity; Neuroprotective Agents; Phospholipase D; Phosphoric Diester Hydrolases; Phosphorylation; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Signal Transduction; Synapses

NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in the development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioral and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801-triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile.

Topics: Age Factors; Animals; Antidepressive Agents; Caspase 3; Dizocilpine Maleate; Drug Interactions; Female; Gyrus Cinguli; Hallucinogens; HSP70 Heat-Shock Proteins; Male; Mice; Motor Activity; Nerve Degeneration; Phenols; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate

Whereas kainate (KA)-induced neurodegeneration has been intensively investigated, the contribution of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in neuronal Ca2+ overload ([Ca2+]i) is still controversial. Using Ca2+ imaging and patch-clamp techniques, we found different types of Ca2+ entry in cultured rat cortical neurons. The presence of Ca2+ in the extracellular solution was required to generate the [Ca2+]i responses to 30 μM N-methyl-d-aspartate (NMDA) or KA. The dynamics of NMDA-induced [Ca2+]i responses were fast, while KA-induced responses developed slower reaching high [Ca2+]i. Ifenprodil, a specific inhibitor of the GluN2B subunit of NMDARs, reduced NMDA-induced [Ca2+]i responses suggesting expression of GluN1/GluN2B receptors. Using IEM-1460, a selective blocker of Ca(2+)-permeable GluA2-subunit lacking AMPARs, we found three neuronal responses to KA: (i) IEM-1460 resistant neurons which are similar to pyramidal neurons expressing Ca(2+)-impermeable GluA2-rich AMPARs; (ii) Neurons exhibiting nearly complete block of both KA-induced currents and [Ca2+]i signals by IEM-1460 may represent interneurons expressing GluA2-lacking AMPARs and (iii) neurons with moderate sensitivity to IEM-1460. Ouabain at 1 nM prevented the neuronal Ca2+ overload induced by KA. The data suggest, that cultured rat cortical neurons maintain functional phenotypes of the adult brain cortex, and demonstrate the key contribution of the Na/K-ATPase in neuroprotection against KA excitotoxicity.

Topics: Adamantane; Animals; Calcium; Calcium Signaling; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Female; In Vitro Techniques; Kainic Acid; Nerve Degeneration; Neurons; Ouabain; Patch-Clamp Techniques; Piperidines; Pregnancy; Rats; Rats, Wistar; Receptors, AMPA

Parkinson's disease is the second most prevalent neurodegenerative disease in the world. Its treatment is limited so far to the management of parkinsonian symptoms with L-DOPA (LD). The long-term use of LD is limited by the development of L-DOPA-induced dyskinesias and dystonia. However, recent studies have suggested that pharmacological targeting of the endocannabinoid system may potentially provide a valuable therapeutic tool to suppress these motor alterations. In the present study, we have explored the behavioral (L-DOPA-induced dyskinesias severity) and cytological (substantia nigra compacta neurons and striatum neuropil preservation) effects of the oral coadministration of LD and rimonabant, a selective antagonist of CB1 receptors, in the 6-hydroxydopamine rat model of Parkinson's disease. Oral coadministration of LD (30 mg/kg) and rimonabant (1 mg/kg) significantly decreased abnormal involuntary movements and dystonia, possibly through the conservation of some functional tyrosine hydroxylase-immunoreactive dopaminergic cells, which in turn translates into a well-preserved neuropil of a less denervated striatum. Our results provide anatomical evidence that long-term coadministration of LD with cannabinoid antagonist-based therapy may not only alleviate specific motor symptoms but also delay/arrest the degeneration of striatal and substantia nigra compacta cells.

Topics: Administration, Oral; Animals; Cannabinoid Receptor Antagonists; Corpus Striatum; Dihydroxyphenylalanine; Disease Models, Animal; Dopamine Agents; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Male; Nerve Degeneration; Neuropil; Oxidopamine; Parkinsonian Disorders; Piperidines; Pyrazoles; Rats; Rimonabant; Substantia Nigra; Tyrosine 3-Monooxygenase

Endocannabinoids exert numerous effects in the CNS under physiological and pathological conditions. The aim of the present study was to examine whether the endocannabinoid N-arachidonoyldopamine (NADA) may protect neurons in excitotoxically lesioned organotypic hippocampal slice cultures (OHSC). OHSC were excitotoxically lesioned by application of N-methyl-d-aspartate (NMDA, 50 μM) for 4 h and subsequently treated with different NADA concentrations (0.1 pM-50 μM) alone or in combination with cannabinoid receptor antagonists. NADA protected dentate gyrus granule cells and caused a slight reduction in the number of microglial cells. The number of degenerated neurons significantly decreased between 100 pM and 10 μM NADA (p < 0.05). To identify the responsive receptor type of NADA mediated neuroprotection, we applied the cannabinoid (CB) receptor 1 (CB(1)) inverse agonist/antagonist AM251, CB(2) inverse agonist/antagonist AM630, abnormal-cannabidiol (abn-CBD)-sensitive receptor antagonist O-1918, transient receptor potential channel V1 (TRPV1) antagonist 6-iodonordihydrocapsaicin and A1 (TRPA1) antagonist HC-030031. Neuroprotective properties of low (1 nM) but not high (10 μM) NADA concentrations were solely blocked by AM251 and were absent in CB(1)(-/-) mice. AM630, O-1918, 6-iodonordihydrocapsaicin and HC-030031 showed no effects at all NADA concentrations applied. Our findings demonstrate that NADA protects dentate gyrus granule cells by acting via CB(1). NADA reduced the number of microglial cells at distinct concentrations. TRPV1 and TRPA1 were not involved in NADA mediated neuroprotection. Thus, our data implicate that NADA mediated activation of neuronal CB(1) may serve as a novel pharmacological target to mitigate symptoms of neuronal damage.

Topics: Animals; Arachidonic Acids; Cells, Cultured; Dopamine; Excitatory Postsynaptic Potentials; Hippocampus; Mice; Nerve Degeneration; Neurons; Neuroprotective Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

While endocannabinoid modulation of both GABAergic and glutamatergic synaptic transmission and plasticity has been extensively investigated, our understanding of the role of endocannabinoids in protecting neurons from harmful insults remains limited. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous ligand and a full agonist for cannabinoid receptors, exhibits anti-inflammatory and neuroprotective effects via a CB1 receptor (CB1R)-mediated mechanism. However, it is still not clear whether 2-AG is also able to protect neurons from β-amyloid (Aβ)-induced neurodegeneration. Here, we demonstrate that exogenous application of 2-AG significantly protected hippocampal neurons in culture against Aβ-induced neurodegeneration and apoptosis. This neuroprotective effect was blocked by SR141716 (SR-1), a selective CB1R antagonist, but not by SR144528 (SR-2), a selective CB2R antagonist, or capsazepine (CAP), a selective transient receptor potential cation channels, subfamily V, member 1 (TRPV1) receptor antagonist. To determine whether endogenous 2-AG is capable of protecting neurons from Aβ insults, hippocampal neurons in culture were treated with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-AG. MAGL inhibition that elevates endogenous levels of 2-AG also significantly reduced Aβ-induced neurodegeneration and apoptosis. The 2-AG-produced neuroprotective effects appear to be mediated via CB1R-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) phosphorylation and cyclooxygenase-2 (COX-2) expression. Our results suggest that elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer's disease.

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Arachidonic Acids; Benzodioxoles; Biphenyl Compounds; Camphanes; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Capsaicin; Cell Culture Techniques; Drug Interactions; Endocannabinoids; Glycerides; Hippocampus; Monoacylglycerol Lipases; Nerve Degeneration; Peptide Fragments; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction

Excess glutamate release and stimulation of post-synaptic glutamatergic receptors have been implicated in the pathophysiology of many neurological diseases. The hippocampus, and the pyramidal cell layer of the cornu ammonus 1 (CA1) region in particular, has been noted for its selective sensitivity to excitotoxic insults. The current studies examined the role of N-methyl-D-aspartate (NMDA) receptor subunit composition and sensitivity to stimulatory effects of the polyamine spermidine, an allosteric modulator of NMDA NR2 subunit activity, in hippocampal CA1 region sensitivity to excitotoxic insult. Organotypic hippocampal slice cultures of 8 day-old neonatal rat were obtained and maintained in vitro for 5 days. At this time, immunohistochemical analysis of mature neuron density (NeuN); microtubule associated protein-2(a,b) density (MAP-2); and NMDA receptor NR1 and NR2B subunit density in the primary cell layers of the dentate gyrus (DG), CA3, and CA1 regions, was conducted. Further, autoradiographic analysis of NMDA receptor distribution and density (i.e. [(125)I]MK-801 binding) and spermidine (100 microM)-potentiated [(125)I]MK-801 binding in the primary cell layers of these regions was examined. A final series of studies examined effects of prolonged exposure to NMDA (0.1-10 microM) on neurodegeneration in the primary cell layers of the DG, CA3, and CA1 regions, in the absence and presence of spermidine (100 microM) or ifenprodil (100 microM), an allosteric inhibitor of NR2B polypeptide subunit activity. The pyramidal cell layer of the CA1 region demonstrated significantly greater density of mature neurons, MAP-2, NR1 and NR2B subunits, and [(125)I]MK-801 binding than the CA3 region or DG. Twenty-four hour NMDA (10 microM) exposure produced marked neurodegeneration (approximately 350% of control cultures) in the CA1 pyramidal cell region that was significantly reduced by co-exposure to ifenprodil or DL-2-Amino-5-phosphonopentanoic acid (APV). The addition of spermidine significantly potentiated [(125)I]MK-801 binding and neurodegeneration induced by exposure to a non-toxic concentration of NMDA, exclusively in the CA1 region. This neurodegeneration was markedly reduced with co-exposure to ifenprodil. These data suggest that selective sensitivity of the CA1 region to excitotoxic stimuli may be attributable to the density of mature neurons expressing polyamine-sensitive NR2B polypeptide subunits.

Topics: Animals; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Dentate Gyrus; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hippocampus; In Vitro Techniques; Male; N-Methylaspartate; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Piperidines; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spermidine; Valine

The removal of pathologically generated free radicals produced during ischemia, reperfusion and intracranical hemorrhage seems to be a viable approach to neuroprotection. However, at present, no neuroprotective agent has proven effective in focal ischemic stroke phase III trials, despite the encouraging data in animal models. This study aimed to explore the effect of the brain penetrant low molecular weight radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC) in neurological damage subsequent to ischemia-reperfusion injury in Mongolian gerbils. We examined the intraperitoneal effects of IAC on temporary bilateral common carotid artery occlusion (BCCO) by means of morphological and histological analysis of the hippocampus. Significant dose-dependent protective effects of IAC (1 to 10mg/kg b.w.) against neuropathological and morphological brain changes were seen when administered i.p. 1h before temporary BCCO in Mongolian gerbils. When administered up to 6h after BCCO, IAC actually reverses the neurodegenerative processes (e.g. hippocampal cell viability) induced by ischemia in a dose-dependent fashion. Data show that IAC is highly effective in protecting and preventing oxidative brain damage associated with cerebral flow disturbances. It is also effective even in late treatment of the insult, emphasizing its potential role for the management of ischemic stroke patients.

Topics: Animals; Brain Damage, Chronic; Brain Infarction; Brain Ischemia; Carotid Stenosis; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers; Gerbillinae; Hippocampus; Infusions, Parenteral; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Piperidines; Treatment Outcome

Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimer's disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimer's disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Animals; Aziridines; Benzodioxoles; Choline; Cognition Disorders; Donepezil; Hippocampus; Indans; Injections, Intraventricular; Lipid Peroxidation; Male; Malondialdehyde; Maze Learning; Nerve Degeneration; Neuromuscular Blocking Agents; Neuroprotective Agents; Nootropic Agents; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Space Perception; Thailand

To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia.. MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.. A dementia clinic at Washington University School of Medicine.. Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician.. Hippocampal volume loss and surface deformation.. There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations.. Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Topics: Aged; Alzheimer Disease; Atrophy; Brain Mapping; Cholinesterase Inhibitors; Cognition Disorders; Cohort Studies; Disease Progression; Donepezil; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; Indans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nerve Degeneration; Piperidines; Time Factors; Treatment Outcome

Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Donepezil; Humans; Indans; Mice; Mice, Inbred C3H; Mice, Transgenic; Mutation; Nerve Degeneration; Piperidines; Synapses; tau Proteins; Tauopathies

There is accumulating evidence that excitotoxicity and oxidative stress resulting from excessive activation of glutamate (N-methyl-D-aspartate) NMDA receptors are major participants in striatal degeneration associated with 3-nitropropionic acid (3NP) administration. Although excitotoxic and oxidative mechanisms are implicated in 3NP toxicity, there are conflicting reports as to whether NMDA receptor antagonists attenuate or exacerbate the 3NP-induced neurodegeneration. In the present study, we investigated the involvement of NMDA receptors in striatal degeneration, protein oxidation and motor impairment following systemic 3NP administration. We examined whether NMDA receptor antagonists, memantine and ifenprodil, influence the neurotoxicity of 3NP. The development of striatal lesion and protein oxidation following 3NP administration is delayed by memantine but not affected by ifenprodil. However, in behavioral experiments, memantine failed to improve and ifenprodil exacerbated the motor deficits associated with 3NP toxicity. Together, these findings suggest caution in the application of NMDA receptor antagonists as a neuroprotective agent in neurodegenerative disorders associated with metabolic impairment.

Topics: Adenosine Diphosphate; Animals; Corpus Striatum; Dizocilpine Maleate; Drug Interactions; Male; Memantine; Motor Activity; Nerve Degeneration; Neuroprotective Agents; Nitro Compounds; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Propionates; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tyrosine

Previously, we showed that in rat cortical neurons, chronic donepezil treatment (10 microM, 4 days) up-regulates nicotinic receptors (nAChR) and makes neurons more sensitive to the neuroprotective effect of donepezil. Here we examined the mechanism of donepezil-induced neuroprotection in neurons chronically treated with donepezil. The mechanism of neuroprotection was examined under different conditions of exposure to glutamate, acute and moderate, that induce cell death associated with necrotic and apoptotic cell death, respectively. Concomitant treatment with antagonists of nAChRs but not muscarinic receptors inhibited donepezil pretreatment-induced neuroprotection against acute glutamate treatment-induced death. Donepezil pretreatment prevented acute glutamate- and ionomycin-induced neurotoxicity, but not S-nitrosocysteine-induced neurotoxicity, suggesting that donepezil protects neurons via nAChR at levels before nitric oxide synthase activation against acute glutamate neurotoxicity. Concomitant treatment with antagonists of nAChR or phosphatidylinositol 3-kinase (PI3K) signaling inhibitors significantly inhibited neuroprotection against moderate glutamate neurotoxicity and decreased the phosphorylation level of Akt. Neuroprotection was also inhibited by treatment with inhibitor of mitogen-activated protein kinase (MAPK) kinase. These results suggest that donepezil protects neurons against moderate glutamate neurotoxicity via nAChR-PI3K-Akt and MAPK signaling pathways. This study provides novel insight into the mechanism of donepezil-induced neuroprotection that involves nAChR up-regulation.

Topics: Animals; Apoptosis; Cells, Cultured; Cerebral Cortex; Cholinesterase Inhibitors; Cytoprotection; Donepezil; Enzyme Inhibitors; Glutamic Acid; Indans; Ionomycin; Ionophores; MAP Kinase Signaling System; Necrosis; Nerve Degeneration; Neurons; Neuroprotective Agents; Nicotinic Antagonists; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, Nicotinic; Signal Transduction

We previously reported that delayed administration of the general cyclin-dependent kinase inhibitor flavopiridol following global ischemia provided transient neuroprotection and improved behavioral performance. However, it failed to provide longer term protection. In the present study, we investigate the ability of delayed flavopiridol in combination with delayed minocycline, another neuroprotectant to provide sustained protection following global ischemia. We report that a delayed combinatorial treatment of flavopiridol and minocycline provides synergistic protection both 2 and 10 weeks following ischemia. However, protected neurons in the hippocampal CA1 are synaptically impaired as assessed by electrophysio logical field potential recordings. This is likely because of the presence of degenerated processes in the CA1 even with combinatorial therapy. This indicates that while we have addressed one important pre-clinical parameter by dramatically improving long-term neuronal survival with delayed combinatorial therapy, the issue of synaptic preservation of protected neurons still exists. These results also highlight the important observation that protection does not always lead to proper function.

Topics: Animals; Anti-Bacterial Agents; Brain Infarction; Brain Ischemia; Dendrites; Disease Models, Animal; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Flavonoids; Hippocampus; Male; Minocycline; Nerve Degeneration; Neural Pathways; Neurons; Neuroprotective Agents; Piperidines; Protein Kinase Inhibitors; Rats; Rats, Wistar; Synaptic Transmission; Time Factors; Treatment Outcome

In this study we evaluated the effect of donepezil on the neurodegeneration and behavioral impairments induced by mild traumatic brain injury (MTBI). Donepezil is an acetylcholinesterase inhibitor that is used to treat Alzheimer's disease. Donepezil was given orally to rats subjected to MTBI. Treatment with a single oral dose of donepezil (12mg/kg) immediately after injury significantly attenuated MTBI-induced neuronal death and cognitive impairment as measured by preservation of neurons in the CA1 region of the hippocampus and a water maze test respectively. However, these neuroprotective effects were prevented by concomitant injection of mecamylamine, a nicotinic acetylcholine-receptor (nAChR) antagonist, indicating that protection is mediated by nAChR activation.

Topics: Animals; Brain; Brain Concussion; Brain Injuries; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Hippocampus; Indans; Male; Maze Learning; Memory Disorders; Nerve Degeneration; Neuroprotective Agents; Nicotinic Agonists; Nicotinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Treatment Outcome

Activation of 5-HT4 receptors has been shown to improve memory processes in preclinical cognition models, suggesting potential utility of 5-HT4 agonists for the symptomatic treatment of Alzheimer's disease (AD). Recent studies have shown that 5-HT4 agonists also increase the secretion of the non-amyloidogenic soluble amyloid precursor protein-alpha (sAPPalpha). In the present study, we demonstrated that a selective 5-HT4 partial agonist, RS67333, inhibited the generation of beta-amyloid peptide (Abeta) in primary cortical cultures of Tg2576 transgenic mice expressing human APP(K670N/M671L). Furthermore, treatments with RS67333 selectively increased the survival of transgenic neurons in a dose-dependent manner, which was inhibited by 5-HT4 antagonists. These and previous data collectively suggest that the 5-HT4 receptor may be an effective therapeutic target for AD, providing both symptomatic improvements and neuroprotection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Cell Survival; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Male; Mice; Mice, Transgenic; Nerve Degeneration; Neurons; Neuroprotective Agents; Peptide Fragments; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Synaptic Transmission; Treatment Outcome

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Topics: Adrenergic alpha-Antagonists; Animals; Avoidance Learning; Behavior, Animal; Dextromethorphan; Ethylenediamines; Immunohistochemistry; Learning Disabilities; Maze Learning; Memory; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Phencyclidine; Receptors, sigma; Seizures; Sigma-1 Receptor; Trimethyltin Compounds

One of the few currently approved therapies for Alzheimer's disease (AD) consists in the administration of acetylcholinesterase inhibitors, which enhances the lifetime of the neurotransmitter acetylcholine. Despite numerous studies on the symptomatic effect of acetylcholinesterase inhibitors, there is as yet no direct morphological evidence to indicate that they have a neurorestorative action. We investigated the effect of the acetylcholinesterase inhibitor donepezil administered subcutaneously in a rat model of partial unilateral cortical devascularization that induces a loss of the cortical cholinergic terminal network and a retrograde degeneration of the cholinergic projections that originate in the nucleus basalis. For 6 weeks, lesioned and sham-operated rats received a subcutaneous infusion of donepezil (2 mg/kg/day) or vehicle, delivered by osmotic minipumps implanted 2 weeks before the cortical devascularization. In lesioned rats, donepezil treatment increased the number and the size of vesicular acetylcholine transporter immunoreactive boutons in comparison to vehicle treatment. Donepezil had no observable effect on any of these parameters in sham-operated animals. These results show that donepezil mitigates cholinergic neuronal degeneration in vivo. This suggests a neuroplastic activity of this drug and provides evidence for a potential use of donepezil as a disease modifier in neurodegenerative diseases such as AD.

Topics: Acetylcholine; Alzheimer Disease; Animals; Basal Nucleus of Meynert; Cerebral Cortex; Cholinergic Fibers; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Growth Cones; Indans; Male; Nerve Degeneration; Nerve Regeneration; Neural Pathways; Neuronal Plasticity; Piperidines; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Stroke; Vesicular Acetylcholine Transport Proteins

Success in treating patients with progressive supranuclear palsy and corticobasal degeneration remains exceedingly low. This finding probably relates to the widespread distribution of the pathological changes that account for the varied and complex spectrum of clinical manifestations. Dopaminergic drugs are regularly used for the parkinsonian features; however, these rarely result in more than modest benefit, and when better or sustained responses are obtained, as sometimes occurs in progressive supranuclear palsy, the clinical features are atypical and diagnosis is often delayed or not made in life. A variety of other treatments have been used in both disorders, sometimes directed at other specific features such as dystonia or myoclonus, and these treatments will be reviewed. Greater success in treating these disorders will require advances in our understanding of their cause(s) or the pathogenetic mechanisms underlying the neurodegenerative processes. The similarities in the molecular pathology of these four-repeat tauopathies suggests that important advances in the management of one will have a definite impact on the treatment of the other.

Topics: Amantadine; Cerebral Cortex; Cholinesterase Inhibitors; Corpus Striatum; Donepezil; Dopamine Agents; Dopamine Agonists; Dystonia; Globus Pallidus; Humans; Indans; Levodopa; Nerve Degeneration; Piperidines; Substantia Nigra; Supranuclear Palsy, Progressive

We investigated postischemic alterations in benzodiazepine receptor, D1 dopamine receptor, and muscarinic acetylcholine receptor binding after transient middle cerebral artery (MCA) occlusion in rats using [3H]-flumazenil, [3H]-SCH23390, and [3H]-N-methyl-4-piperidyl benzilate ([3H]-NMPB), respectively, as radioligand. These ligand bindings were determined at 3 and 24 h and at 3 and 7 days after ischemia/reperfusion of MCA by using autoradiographic methods. Ischemic cell injury was clearly detected from 3 h after ischemia/reperfusion and progressively increased from 3-24 h after ischemia/reperfusion of MCA. The area of cell injury reached maximum at 24 h after ischemia/reperfusion of MCA. [3H]-SCH23390 binding was reduced to 47% of the contralateral side at 3 days after ischemia/reperfusion of MCA. After 7 days, [3H]-SCH23390 binding was further reduced by 20% in the striatum. [3H]-NMPB binding was slightly decreased in both the striatum and cerebral cortex at 3 days after ischemia/reperfusion of MCA, and [3H]-NMPB binding in the striatum and cerebral cortex were reduced to 42 and 62% of the contralateral side at 7 days after ischemia/reperfusion of MCA. [3H]-NMPB was also decreased at 24 h. In contrast, [3H]-flumazenil binding was not decreased in the striatum and cerebral cortex within 7 days after ischemia/reperfusion of MCA. These results suggest that [3H]-SCH23390 and [3H]-NMPB binding do not correlate with cell injury by ischemia/reperfusion, although vulnerability to ischemia/reperfusion was observed with these receptors. In addition, central benzodiazepine receptor imaging might be essentially stable to neuronal cell injury induced by transient focal cerebral ischemia in rats, in contrast to the results of PET studies.

Topics: Animals; Autoradiography; Benzazepines; Benzilates; Binding Sites; Binding, Competitive; Cerebral Cortex; Cerebral Infarction; Corpus Striatum; Disease Models, Animal; Down-Regulation; Flumazenil; Infarction, Middle Cerebral Artery; Male; Nerve Degeneration; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D1; Receptors, GABA-A; Receptors, Muscarinic; Reperfusion Injury; Sensitivity and Specificity; Tritium

1 Two cannabinoid receptors, CB1 and CB2, have been identified. The CB1 receptor is preferentially expressed in brain, and the CB2 receptor in cells of leukocyte lineage. We identified the mRNA for the CB1 receptor in human neuroblastoma SH-SY5Y cells, and the mRNA and protein for the CB2 receptor in human microglia and THP-1 cells. 2 Delta(9)-and Delta(8)-tetrahydrocannabinol (THC) were toxic when added directly to SH-SY5Y neuroblastoma cells. The toxicity of Delta(9)- THC was inhibited by the CB1 receptor antagonist SR141716A but not by the CB2 receptor antagonist SR144528. The endogenous ligand anandamide was also toxic, and this toxicity was enhanced by inhibitors of its enzymatic hydrolysis. 3 The selective CB2 receptor ligands JWH-015 and indomethacin morpholinylamide (BML-190), when added to THP-1 cells before stimulation with lipopolysaccharide (LPS) and IFN-gamma, reduced the toxicity of their culture supernatants to SH-SY5Y cells. JWH-015 was more effective against neurotoxicity of human microglia than THP-1 cells. The antineurotoxic activity of JWH-015 was blocked by the selective CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A. This activity of JWH-015 was synergistic with that of the 5-lipoxygenase (5-LOX) inhibitor REV 5901. 4 Cannabinoids inhibited secretion of IL-1beta and tumor necrosis factor-alpha (TNF-alpha) by stimulated THP-1 cells, but these effects could not be directly correlated with their antineurotoxic activity. 5 Specific CB2 receptor ligands could be useful anti-inflammatory agents, while avoiding the neurotoxic and psychoactive effects of CB1 receptor ligands such as Delta(9)-THC.

Topics: Astrocytes; Camphanes; Cannabinoid Receptor Modulators; Cannabinoids; Cell Line; Cytokines; Dronabinol; Formazans; Gene Expression; Humans; Indoles; Indomethacin; L-Lactate Dehydrogenase; Ligands; Microglia; Monocytes; Morpholines; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA, Messenger; Temporal Lobe; Tetrazolium Salts

This study was designed to evaluate the neuroprotective effect of the cannabinoid agonist WIN-55212 after inducing acute severe asphyxia in newborn rats. The left common carotid artery was ligated in anaesthetised 7-day-old Wistar rats, which were then asphyxiated by inhaling 100% nitrogen for 10 min. Pups recovering from asphyxia were s.c. administered vehicle (n=23), WIN-55212 (0.1 mg/kg, n=18), or WIN-55212 plus the CB1 receptor antagonist SR141716 (3 mg/kg, n=10). Pups undergoing a sham operation served as controls (n=12). Coronal sections of the brain were obtained on the 14th day after surgery and observed under light microscope after Nissl or Fluoro-Jade B (FJB) staining, to respectively quantify surviving or degenerating neurones in the CA1 area of the hippocampus and parietal cortex. Acute asphyxia led to early neurone loss amounting to 19% in the hippocampus and 29% in the cortex (both ANOVA P<0.05 vs. control). Delayed neurone loss occurred in the proportions 13% in the hippocampus and 20% in the cortex (both ANOVA P<0.05 vs. control). Neuronal loss was fully prevented by WIN-55212 administration. Co-administration of SR141716 failed to modify the protective effect of WIN-55212 on early neuronal death, but abolished the WIN-55212-induced prevention of delayed neuronal death. We conclude that when administered after acute severe asphyxia in newborn rats, WIN-55212 shows a neuroprotective effect, reducing both early and delayed neurone loss. This effect is achieved through two parallel CB1-dependent and -independent mechanisms.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Benzoxazines; Body Weight; Brain; Cannabinoids; Disease Models, Animal; Female; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Male; Morpholines; Naphthalenes; Nerve Degeneration; Neurons; Neuroprotective Agents; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Staurosporine-induced apoptosis was associated with a 20% cellular survival rate in primary rat forebrain cultures. Treatment with the NR2B subunit-selective NMDA receptor antagonist conantokin-G (0.1-1 microM) increased the survival rate up to 78%. No protection was provided by the nonselective NMDA receptor antagonist dizocilpine (0.01-10 microM) but 34-64% cellular survival was provided by ifenprodil (0.01-10 microM), another NR2B subunit-selective antagonist. These results suggest a novel anti-apoptotic mechanism linked to the NR2B receptor subunit.

Topics: Animals; Apoptosis; Cell Survival; Cells, Cultured; Conotoxins; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Nerve Degeneration; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Staurosporine

The functional loss that often follows injury of the mammalian CNS has been attributed not only to the immediate neural loss, but also to secondary neuronal degeneration caused by toxic biochemical mediators in the environment of the injured nerve. We report here that a high thrombin content, produced as a result of injury-induced activation of prothrombin, appears to be an important mediator of secondary damage. Measurement of post-traumatic neuronal survival in vivo revealed that post-traumatic local application of the thrombin inhibitor N-alpha-(2-naphthylsulphonylglycyl)-4-(D,L)-amidinophenylalanine piperidide acetate in the rat optic nerve subjected to mild partial crush injury left twice as many retinal ganglion cells with functioning axons as in controls. Thus, by readjusting thrombin activity, thereby possibly obtaining a moderate post-traumatic increase and thus gaining the benefit of thrombin without its toxic effects, it may be possible to create an environment that is more favourable for post-traumatic survival.

Topics: Administration, Topical; Animals; Antithrombins; Dipeptides; Nerve Crush; Nerve Degeneration; Neuroprotective Agents; Optic Nerve; Optic Nerve Injuries; Piperidines; Prothrombin; Rats; Rats, Wistar; Thrombin

Increases in extracellular glutamate during cerebral ischemia may play an important role in neuronal injury. Lubeluzole is a novel neuroprotective drug, which in previous in vitro and focal ischemia studies has been shown to inhibit nitric oxide synthesis, to block voltage-gated Na+-ion channels, and to inhibit glutamate release. In this study, we investigated the ability of lubeluzole to inhibit glutamate accumulation during episodes of transient global cerebral ischemia. Twenty-five New Zealand white rabbits were randomized to one of four groups: a normothermic control group; a hypothermic group; a 1.25 mg/kg lubeluzole group; or a 2.5 mg/kg lubeluzole group. The animals were anesthetized, intubated, and ventilated before microdialysis probes were placed in the hippocampus. Lubeluzole was given intravenously 90 min before the onset of ischemia. Esophageal temperature was maintained at 38 degrees C in the control, and lubeluzole treated groups, while the animals in the hypothermia group were cooled to 30 degrees C. A 15-min period of global cerebral ischemia was produced by inflating a neck tourniquet. Glutamate concentrations in the microdialysate were determined using high-performance liquid chromatography (HPLC). During ischemia and early reperfusion, glutamate concentrations increased significantly in the control group and returned to baseline after 15 min of reperfusion. In the lubleuzole 2.5 mg/kg and hypothermia groups, glutamate levels were significantly lower (P<0.05) than in the control group and there was no significant change from baseline levels during the entire experiment. This study suggests that lubeluzole is effective in inhibiting extracellular glutamate accumulation during global cerebral ischemia, and has the potential to produce potent neuroprotection when instituted prior to an ischemic event.

Topics: Action Potentials; Animals; Body Temperature; Brain Ischemia; Cardiovascular Physiological Phenomena; Extracellular Space; Glutamic Acid; Hippocampus; Microdialysis; Nerve Degeneration; Neurons; Neuroprotective Agents; Piperidines; Rabbits; Reperfusion Injury; Respiratory Physiological Phenomena; Thiazoles

Tinuvin 123, a compound used in the manufacture of plastics, has recently been suggested to possibly cause Parkinson's disease (PD). Herein, we revisited this issue by assessing the effect of Tinuvin 123 on dopaminergic neurons of the substantia nigra following its stereotaxic injection in the rat. Twenty-one days post unilateral stereotaxic injection of Tinuvin 123, systemic injection of both apomorphine and amphetamine caused rotations toward the side of the lesion in these rats. Tinuvin 123 produced a small to moderate dose-dependent reduction in striatal levels of dopamine and metabolites on the side of the lesion. This compound also produced dramatic cell loss in the substantia nigra on the side of the lesion. However, the loss of cells lacked the phenotypic specificity for tyrosine hydroxylase (TH)-positive neurons that is expected with a dopaminergic neurotoxin. Indeed, aside from a robust glial reaction, both TH-positive and glutamic acid dehydrogenase (GAD)-positive neurons were destroyed, and near the site of the injection, there was complete tissue destruction. This study indicates that, using this mode of injection, Tinuvin 123 exerts a dramatic tissue toxicity without any evidence of specificity for dopaminergic neurons. Thus, our data argues against a role for Tinuvin 123 as an environmental toxin causing a clinical condition characterized by the selective loss of dopaminergic neurons as seen in PD.

Topics: Animals; Astrocytes; Behavior, Animal; Calcium Channel Blockers; Decanoic Acids; Dopamine; Environmental Pollutants; Functional Laterality; gamma-Aminobutyric Acid; Glial Fibrillary Acidic Protein; Glutamate Decarboxylase; Male; Movement; Neostriatum; Nerve Degeneration; Neural Pathways; Neurons; Neurotoxins; Occupational Exposure; Parkinson Disease, Secondary; Piperidines; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; Survival Rate; Tyrosine 3-Monooxygenase

The regional cerebral metabolic rate of [11C]N-methyl-4-piperidyl acetate, which is nearly proportional to regional cerebral acetylcholinesterase (AChE) activity, was measured by dynamic positron emission tomography in 20 healthy subjects with a wide age range (24-89 years). Quantitative measurement was achieved using a kinetic model which consisted of arterial plasma and cerebral tissue compartments. The plasma input function was obtained using thin-layer chromatography and an imaging phosphor plate system at frequent sampling intervals to catch the rapid metabolism of the tracer in the blood. The distribution of the rate constant k3, an index of AChE activity, agreed well with reported post-mortem AChE distribution in the cerebral cortex (0.067-0.097 min-1) and thalamus (0.268 min-1), where AChE activity was low to moderate. The k3 values in the striatum and cerebellum, where AChE activity was very high, did not respond linearly to AChE activity because of increased flow dependency. No significant effect of age was found on AChE activity of the cerebral cortex, suggesting that the ascending central cholinergic system is preserved in normal aging. This study has shown that quantitative measurement of enzyme activity in the living brain is possible through appropriate modelling of tracer kinetics and accurate measurement of the input function. The method should be applicable to patients with Alzheimer's disease and those with other kinds of dementia whose central cholinergic system has been reported to be disturbed.

Topics: Acetates; Acetylcholinesterase; Adult; Aged; Aged, 80 and over; Aging; Brain; Carbon Radioisotopes; Cerebral Cortex; Chromatography, Thin Layer; Female; Humans; Male; Middle Aged; Nerve Degeneration; Piperidines; Reference Values; Thalamus; Tomography, Emission-Computed

NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521. NS521 did not preserve the neurites of the rescued cells, which, otherwise, appeared to be healthy and were able to regenerate when serum and nerve growth factor were added back to the culture. In vivo, NS521 provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. A neuroprotective effect of NS521 in the peripheral nervous system also was observed in rats after transection of the sciatic nerve, where daily treatment with NS521 was found to inhibit retrograde degeneration of the transected nerve. The neuroprotective effect of NS521 is unlikely to be mediated through neurotrophin receptors, such as TrkA, because NS521 did not induce phosphorylation of the 44- and 42-kDa isoforms of mitogen-activated protein kinases (ERK1/2) in PC12 cells.

Topics: Animals; Benzimidazoles; Calcium-Calmodulin-Dependent Protein Kinases; Cell Survival; Culture Media; DNA Fragmentation; Gerbillinae; Ischemic Attack, Transient; Male; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neurons; Neuroprotective Agents; PC12 Cells; Phosphorylation; Piperidines; Rats; Rats, Wistar

Topics: Action Potentials; Analgesics; Animals; Basal Ganglia; Benzoxazines; Bicuculline; Cannabinoids; Cyclohexanols; Dopamine; Dopamine Agonists; Electrophysiology; GABA Antagonists; gamma-Aminobutyric Acid; Morpholines; Motor Neurons; Naphthalenes; Nerve Degeneration; Neurotransmitter Agents; Oxidopamine; Piperidines; Pyrazoles; Quinpirole; Rats; Rimonabant; Sympatholytics; Thalamic Nuclei

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.

Topics: Animals; Cell Death; Cells, Cultured; Genes, fos; Hippocampus; Male; Mice; N-Methylaspartate; Nerve Degeneration; Piperidines; Rats; Structure-Activity Relationship

In order to study the control mechanism of cholecystokinin (CCK) contents of the rat brain mediated by pre-synaptic receptors in dopamine (DA) neurons, R(+) and S(-) compounds of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), which are selective pre-synaptic dopaminergic agents, were administered in rats at low and high doses. CCK-8-like immunoreactivity (CCK-8 LI) was measured in the medial frontal cortex. In another experiment, a neurotoxin, N-methyl-D-aspartic acid (NMDA) was used to degenerate efferent CCK neurons and CCK interneurons of the medial frontal cortex, followed by an intraperitoneal administration of apomorphine hydrochloride (APO) to study the effect on CCK-8 LI via the pre-synaptic DA receptor. According to the results of these experiments, CCK-8 LI was increased in the medial frontal cortex in response to the stimulation of pre-synaptic DA receptor, suggesting a control of CCK-8 release, at least in part, by the pre-synaptic DA receptor.

Topics: Animals; Apomorphine; Behavior, Animal; Cholecystokinin; Dopamine; Dopamine Agents; In Vitro Techniques; Male; Microinjections; N-Methylaspartate; Nerve Degeneration; Neurons; Piperidines; Prefrontal Cortex; Rats; Rats, Wistar; Receptors, Dopamine

Injection of the N-methyl-D-aspartate receptor agonist quinolinate, or N-methyl-D-aspartate itself, into the rat brain produces neurodegeneration which can be prevented by N-methyl-D-aspartate receptor antagonists administered up to 5 h after excitotoxin injection. The present study was designed to investigate aspects of the mechanisms involved in this delayed form of neurodegeneration. Following its injection into the rat striatum, extracellular levels of [3H]quinolinate were monitored using a microdialysis probe located 1 mm from the site of injection. Peak concentrations were observed 10-20 min after injection and [3H]quinolinate levels decayed in a biexponential fashion, the initial component having an apparent t1/2 of 13.7 +/- 5.2 min (n = 3). Estimations of the extracellular concentrations of quinolinate after an injection of 200 nmol indicated a peak level of 13.7 +/- 6.0 mM (n = 3) at 10-20 min which declined to 1.2 +/- 0.13 mM (n = 3) by 2 h and substantial levels were present up to 5 h, the period over which N-methyl-D-aspartate receptor antagonists are effective in this model. Administration of dizocilpine at 1, 2, 3 or 5 h after injection of 100, 200 or 400 nmol quinolinate resulted in a similar temporal profile of neuroprotection, as assessed by measuring the activities of choline acetyltransferase and glutamate decarboxylase in striatal homogenates, which was independent of the degree of neurodegeneration produced by the different excitotoxin doses. Overall, these results suggest that the neuronal degeneration caused by quinolinate in vivo is critically dependent upon events occurring after the initial peak of excitoxin levels in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Convulsants; Corpus Striatum; Dialysis; Diazepam; Dizocilpine Maleate; Glutamate Decarboxylase; Haloperidol; Ibotenic Acid; Injections; Male; Nerve Degeneration; Pipecolic Acids; Piperazines; Piperidines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Stereotaxic Techniques

The in vivo efficacies and potencies of various excitatory amino acid agonists in inducing cholinergic neuronal degeneration were compared following unilateral injections into the rat striatum. Kainic acid (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), ibotenic acid (IBO), and N-methyl-D-aspartic acid (NMDA) all produced dose-related decreases in choline acetyltransferase (ChAT) activity. The relative order of potency was KA greater than AMPA greater than IBO greater than NMDA. Quisqualic acid (QUIS) was about as potent as NMDA, but the maximal decrease in ChAT activity was less (36%). N-acetylaspartyl-L-glutamate (NAAG) did not significantly decrease ChAT activity when up to 1,000 nmoles was injected. Approximate equitoxic doses of agonists were then used to examine the ability of i.p. administered CGS-19755 and MK-801 to prevent in vivo excitatory amino acid-induced cholinergic and GABAergic neuronal degeneration. NMDA-induced decreases in ChAT and glutamic acid decarboxylase (GAD) activities were prevented by CGS-19755 (10-40 mg/kg) and MK-801 (1-10 mg/kg). CGS-19755 (40 mg/kg) and MK-801 (10 mg/kg) did not prevent loss of ChAT or GAD induced by KA or AMPA, but did prevent the degenerative effects of IBO. This study shows that CGS-19755 and MK-801, two NMDA receptor antagonists that act by different mechanisms, are completely selective following systemic administration. Moreover, the in vivo excitotoxic effects of IBO are mediated at NMDA receptor sites that are blocked by these compounds.

Topics: Animals; Aspartic Acid; Choline O-Acetyltransferase; Cholinergic Fibers; Corpus Striatum; Dibenzocycloheptenes; Dizocilpine Maleate; gamma-Aminobutyric Acid; Ibotenic Acid; Male; N-Methylaspartate; Nerve Degeneration; Oxazoles; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The pathological findings in four nerves and muscles and in one skin biopsies from four patients treated with perhexiline maleate for angina pectoris are reported. In every case, a muscular denervation atrophy and a decrease in the large diameter myelinated fibers were observed. Only one case showed a decrease of the total number of myelinated fibers, on quantitative studies. The electron microscopic study of each nerve displayed findings consistent with a predominant schwannian degeneration, associated with a few onion bulbs formations and, in two cases, with a mild wallerian degeneration. The most striking finding consisted in the presence of polymorphous membrane-bound inclusions reminding the morphology of lysosomal complex lipids. These structures were very abundant in Schwann cells, but they were seen also in fibrocytes, endothelial and pericytic cells. Similar inclusions were present in the single muscle and skin biopsies studied by electron microscopy. In the muscle, they were seen in muscular cells as well as in endothelial and pericytic cells. In the skin, similar inclusions were observed in endothelial, smooth muscle and sweat gland cells. These inclusions were difficult to identify in one micron thick sections, emphazing the need of ultrastructural study for diagnostic purposes.

Topics: Aged; Angina Pectoris; Female; Humans; Male; Microscopy, Electron; Middle Aged; Muscles; Muscular Atrophy; Nerve Degeneration; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Piperidines; Schwann Cells; Skin

The pressure response of the rat urinary bladder to electrical stimulation of the pelvic nerve at a low stimulation frequency was found to be almost completely atropine resistant. However, the response to stimulation of the degenerating pelvic nerve 20-30 h after section of the nerve postganglionically using maximal stimulation frequency was totally abolished by atropine or the parasympatholytic agent Hoechst 9980. The responses were not affected by hexamethonium or dihydroergotamine, but were potentiated by eserine. The non-adrenergic portion of the bladder response to stimulation of the degenerating hypogastric nerves was also abolished by atropine or Hoechst 9980. It is concluded that the transmitter activating the detrusor muscle at stimulation of the pelvic nerve or the non-adrenergic part of the hypogastric nerve probably is acetylcholine.

Topics: Amides; Animals; Atropine; Denervation; Depression, Chemical; Dihydroergotamine; Diphenylacetic Acids; Electric Stimulation; Ganglia; Hexamethonium Compounds; Male; Muscle Contraction; Nerve Degeneration; Parasympathetic Nervous System; Physostigmine; Piperidines; Pressure; Rats; Stimulation, Chemical; Sympathetic Nervous System; Urinary Bladder

Topics: Acetamides; Animals; Atropine; Autonomic Fibers, Postganglionic; Chloralose; Hexamethonium Compounds; Male; Muscle Contraction; Nerve Degeneration; Physostigmine; Piperidines; Pressure; Rats; Sympathectomy; Synaptic Transmission; Time Factors; Urinary Bladder