benzofurans and Nerve-Degeneration

In this study, we evaluated the protective effects of damaurone D (DaD), a dihydropyranoaurone compound, on dopaminergic (DA) neurodegeneration in Caenorhabditis elegans. The results showed that DaD treatment could successfully increase the survival rate of the worms under MPP

Topics: Animals; Animals, Genetically Modified; Benzofurans; Caenorhabditis elegans; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Nerve Degeneration; Neuroprotective Agents; Parkinson Disease

Pharmacological compounds that release nitric oxide (NO) have been recognized as the potential therapeutic agents for acute stroke. (S)-ZJM-289 is a novel NO-releasing derivative of 3-n-butylphthalide (NBP) with enhanced anti-platelet and anti-thrombotic actions. The present study was performed to investigate the neuroprotective effects and related mechanisms of (S)-ZJM-289 on ischemic neuronal injury in vitro and in vivo. Primary cortical neuronal cultures were exposured to oxygen-glucose deprivation followed by recovery (OGD/R), a model of ischemia-like injury, and treated with (S)-ZJM-289 before OGD. In vitro results showed that (S)-ZJM-289 attenuated OGD/R-induced neuronal injury, which was associated with the maintenance of mitochondrial integrity and function by alleviating intracellular calcium overload and reactive oxygen species (ROS) accumulation, preventing mitochondrial membrane depolarization and preserving respiratory chain complexes activities. Moreover, (S)-ZJM-289 treatment suppressed mitochondrial release of cytochrome c (cyt c) and nuclear translocation of apoptosis-inducing factor (AIF), thereby blocking mitochondria-mediated cell death, which may be partially mediated by up-regulation of Hsp70. The neuroprotection by (S)-ZJM-289 was also studied using a model of middle cerebral artery occlusion (MCAO). Oral administration of (S)-ZJM-289 at the onset of reperfusion for 3d significantly reduced the brain infarct size, improved neurological deficit and prevented neuronal loss and apoptosis. In current study, (S)-ZJM-289 appears to be more potent in ischemic neuroprotection than NBP, in particular at the lower doses, which may be due to the synergistic action of NBP and NO. These findings point to that (S)-ZJM-289 could be an attractive alternative to NBP in preventing the process of ischemia/reperfusion (I/R) injury.

Topics: Animals; Benzofurans; Cell Death; Cinnamates; Disease Models, Animal; Hypoxia-Ischemia, Brain; Male; Mitochondrial Diseases; Nerve Degeneration; Neuroprotective Agents; Nitrates; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The aim of this study was to investigate the protective effect of dl-3-n-butylphthalide (NBP) on brain damage in streptozotocin (STZ)-induced diabetic mice subjected to cerebral ischemia.. we pretreated diabetic mice with NBP orally for 4 weeks prior and 2 days after transient common carotid artery occlusion (CCAO) operation. Immunohistochemistry and transmission electron microscopy were performed to investigate the neuronal loss, astrocytes activation, amyloid-beta (Abeta) protein expression, and autophagy activation.. The results showed that diabetes increased stroke-induced neuronal loss, astrocytes activation, Abeta generation, and autophagy activity, while NBP administration attenuated these changes. Immunofluorescence double staining of Abeta with autophagosome-specific antibody LC3 showed that most elevated Abeta(+) signal was co-localized with LC3(+) signal.. Our finding suggests that NBP attenuates Abeta generation promoted by diabetes in ischemia might act through inhibiting abnormally activated neuronal autophagy. Therefore, treatment with NBP to modulate autophagy might provide a novel therapeutic strategy for diabetes by preventing ischemic brain damage and depressing the risk of post-stroke dementia.

Topics: Amyloid beta-Peptides; Animals; Autophagy; Benzofurans; Brain Ischemia; Dementia; Diabetes Mellitus, Experimental; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Random Allocation; Treatment Outcome

It is shown that l-3-n-butylphthalide (l-NBP), the isomer of dl-NBP (racemic 3-n-butylphthalide, a new anti-cerebral ischemic agent) significantly attenuated cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. In the present study, l-NBP (10 and 30 mg/kg) long-term (3-month) treatment of aged rat (21-month-old) significantly improved the learning and memory capability measured by the Morris water maze test. Hematoxylin-eosin-stained slices showed that both l-NBP at 30 mg/kg, and memantine as control at 20 mg/kg, attenuated the neurodegenerative changes in aged rats. L: -NBP treatment significantly increased the choline acetyltransferase activity and dose-dependently decreased the acetylcholinesterases activity in the hippocampus of aged rats. The immunohistological study demonstrated that expressions of beta-secretase and hyperphosphorylated tau protein were significantly increased in the hippocampus CA1 subfield and parietal cortex in aged rats. However, they were decreased significantly by treatment of l-NBP and memantine for 3 months. Our results indicated that long-term treatment with l-NBP might prevent age-related neurodegenerative changes by modulation of cholinergic system, reduction of phosphorylated tau and maintain structure and morphology of neurons. Therefore, l-NBP might be a potential drug for treatment of senile dementia.

Topics: Aging; Animals; Benzofurans; Dose-Response Relationship, Drug; Female; Male; Nerve Degeneration; Rats; Rats, Wistar; Time Factors

Loss of dorsal root ganglion neuron, or injury to dorsal roots, induces permanent somatosensory defect without therapeutic option. We explored an approach to restoring hind limb somatosensory innervation after elimination of L4, L5 and L6 dorsal root ganglion neurons in rats. Somatosensory pathways were reconstructed by connecting L4, L5 and L6 lumbar dorsal roots to T10, T11 and T12 intercostal nerves, respectively, thus allowing elongation of thoracic ganglion neuron peripheral axons into the sciatic nerve. Connection of thoracic dorsal root ganglion neurons to peripheral tissues was documented 4 and 7 months after injury. Myelinated and unmyelinated fibers regrew in the sciatic nerve. Nerve terminations expressing calcitonin-gene-related-peptide colonized the footpad skin. Retrograde tracing showed that T10, T11 and T12 dorsal root ganglion neurons expressing calcitonin-gene-related-peptide or the neurofilament RT97 projected axons to the sciatic nerve and the footpad skin. Recording of somatosensory evoked potentials in the upper spinal cord indicated connection between the sciatic nerve and the central nervous system. Hind limb retraction in response to nociceptive stimulation of the reinnervated footpads and reversion of skin lesions suggested partial recovery of sensory function. Proprioceptive defects persisted. Delayed somatosensory reinnervation of the hind limb after destruction of lumbar dorsal root neurons in rats indicates potential approaches to reduce chronic disability after severe injury to somatosensory pathways.

Topics: Amidines; Animals; Benzofurans; Calcitonin Gene-Related Peptide; Cell Count; Disease Models, Animal; Electric Stimulation; Electromyography; Evoked Potentials, Somatosensory; Ganglia, Spinal; Immunohistochemistry; Lectins; Lower Extremity; Male; Microscopy, Electron, Transmission; Nerve Degeneration; Nerve Regeneration; Neurofilament Proteins; Neurons; Pain Measurement; Phosphopyruvate Hydratase; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Rhizotomy; Time Factors

Brain injury was induced by intraperitoneal administration of kainic acid (KA, 10 mg/kg). Animals were randomized to receive either IRFI 042 (20 mg/kg i.p.), a lipid peroxidation inhibitor, or its vehicle (NaCl 0.9% DMSO 10% 1 ml/kg i.p.) 30 min before KA administration. A first set of animals was sacrificed 6 h after KA injection to measure malondialdehyde (MDA) content, glutathione-reduced (GSH) levels and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the hippocampus. A second set of animals was sacrificed 48 h after KA administration for histological analysis. All animals were observed for monitoring the behavioral sequelae and for evaluating latency of convulsions. Sham brain injury rats were used as controls. Intraperitoneal administration of IRFI 042 significantly decreased brain MDA (cortex: KA + vehicle = 0.285 +/- 0.04 nmol/mg protein; KA + IRFI 042 = 0.156 +/- 0.02 nmol/mg protein, P < 0.005; hippocampus: KA + vehicle = 0.350 +/- 0.03 nmol/mg protein; KA + IRFI 042 = 0.17 +/- 0.04 nmol/mg protein, P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 7.81 +/- 1 micromol/g protein; KA + IRFI 042 = 12.1 +/- 1 micromol/g protein; P < 0.005) and hippocampus (KA + vehicle = 5 +/- 0.8 micromol/g protein; KA + IRFI 042 = 9.4 +/- 1.8 micromol/g protein; P < 0.005), reduced both brain IL-1beta mRNA expression and oedema, and increased latency of convulsions. Histological analysis showed a reduction of cell damage in IRFI 042-treated samples. The present data indicate that lipid peroxidation inhibition reduces IL-1beta gene expression and protects against kainic acid-induced brain damage.

Topics: Animals; Behavior, Animal; Benzofurans; Brain Edema; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Glutathione; Hippocampus; Interleukin-1; Kainic Acid; Lipid Peroxidation; Male; Malondialdehyde; Nerve Degeneration; Neurotoxins; Oxidative Stress; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures

A deficient control of neuronal repair mechanisms by noradrenergic projections originating from the locus coeruleus may be a critical factor in the progression of neurodegenerative diseases. Blockade of presynaptic inhibitory alpha2-adrenergic autoreceptors can disinhibit this system, facilitating noradrenaline release. In order to test the neuroprotective potential of this approach in a model involving excitotoxicity, the effects of treatments with the alpha2-adreneceptor antagonists, (+)-efaroxan (0.63 mg/kg i.p., thrice daily for 7 days) or (+/-)-idazoxan (2.5 mg/kg i.p., thrice daily for 7 days), were evaluated in rats which received a quinolinic acid-induced lesion of the left striatum. Both drug treatments resulted in a reduced ipsiversive circling response to apomorphine and a reduced choline acetyltransferase deficit in the lesioned striatum. The mechanisms underlying this effect are not known for certain, but may include noradrenergic receptor modulation of glial cell function, growth factor synthesis and release, activity of glutamatergic corticostriatal afferents, and/or events initiated by NMDA receptor activation. These results suggest a therapeutic potential of alpha2-adrenoceptor antagonists in neurodegenerative disorders where excitotoxicity has been implicated.

Topics: Adrenergic alpha-Antagonists; Animals; Apomorphine; Behavior, Animal; Benzofurans; Choline O-Acetyltransferase; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Enzyme Activation; Huntington Disease; Idazoxan; Imidazoles; Male; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2

Many neurons in the medial septal nucleus lose their transmitter-associated enzyme staining following axotomy in the proximal fimbria-fornix (FF), but it is not clear if these neurons have died or persist in a shrunken and subfunctional state. To investigate this further, septal neurons projecting through the FF were labelled with the fluorescent dye, True blue, by retrograde transport from multiple bilateral injection sites in the hippocampus. True blue-labelled neurons and cholinergic neurons immunohistochemically stained for choline acetyltransferase (ChAT) were then quantitatively compared in neighbouring sections through the medial septum 28 days after complete unilateral transections of the proximal FF. The number of True blue and ChAT positive cells ipsilateral to the FF lesion showed significant (P less than 0.001) declines of 51.4% and 71.1%, respectively, relative to the unlesioned side. Cell loss was considerably more severe among large neurons, such that 78.0% and 92.7% of True blue and ChAT labelled cells larger than the normal mean, but only 40.1% and 68.0% of True blue and ChAT labelled cells smaller than the normal mean size were lost. This indicates either that larger neurons were more prone to cell loss, or that some (but not all) large neurons persisted in a shrunken form. Histograms showed no increase in cell number in any of the smaller size categories and a substantial decrease in most cases, indicating that shrinkage alone could not account for the loss of all large neurons. Since True blue can remain present in brainstem cholinergic neurons surviving for over 365 days after axotomy, loss of True blue suggests breakdown of membrane integrity and cell death.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzofurans; Cell Count; Choline O-Acetyltransferase; Cholinergic Fibers; Female; Fluorescent Dyes; Nerve Degeneration; Rats; Rats, Inbred Strains; Septal Nuclei

Topics: Aged; Amiodarone; Benzofurans; Electromyography; Female; Humans; Male; Middle Aged; Motor Neurons; Muscles; Nerve Degeneration; Neural Conduction; Peripheral Nervous System Diseases