1-2-dilinolenoyl-3-(4-aminobutyryl)propane-1-2-3-triol and Disease-Models--Animal

Arsenic is one of the most common heavy metal contaminants found in the environment, particularly in water. We examined the impact of perinatal exposure to relatively low levels of arsenic (50 parts per billion, ppb) on neuroendocrine markers associated with depression and depressive-like behaviors in affected adult C57BL/6J mouse offspring. Whereas most biomedical research on arsenic has focused on its carcinogenic potential, a few studies suggest that arsenic can adversely affect brain development and neural function. Compared to controls, offspring exposed to 50 parts per billion arsenic during the perinatal period had significantly elevated serum corticosterone levels, reduced whole hippocampal CRFR 1 protein level and elevated dorsal hippocampal serotonin 5HT 1A receptor binding and receptor-effector coupling. 5HT 1A receptor binding and receptor-effector coupling were not different in the ventral hippocampal formation, entorhinal or parietal cortices, or inferior colliculus. Perinatal arsenic exposure also significantly increased learned helplessness and measures of immobility in a forced swim task. Taken together, these results suggest that perinatal arsenic exposure may disrupt the regulatory interactions between the hypothalamic-pituitary-adrenal axis and the serotonergic system in the dorsal hippocampal formation in a manner that predisposes affected offspring to depressive-like behavior. These results are the first to demonstrate that relatively low levels of arsenic exposure during development can have long-lasting adverse effects on behavior and neurobiological markers associated with these behavioral changes.

Topics: Analysis of Variance; Animals; Animals, Newborn; Arsenic; Behavior, Animal; Corticosterone; Depression; Disease Models, Animal; Female; gamma-Aminobutyric Acid; Helplessness, Learned; Hippocampus; Male; Mice; Mice, Inbred C57BL; Pregnancy; Prenatal Exposure Delayed Effects; Protein Binding; Receptor, Serotonin, 5-HT1A; Receptors, Corticotropin-Releasing Hormone; Swimming; Triglycerides; Tritium

Alzheimer's disease (AD) is a progressive chronic disorder that leads to cognitive decline. Several studies have associated up-regulation of some of the chemokines and/or their receptors with altered APP processing leading to increased production of beta-amyloid protein (Abeta) and AD pathological changes. However, there is no direct evidence to date to determine whether the altered processing of APP results in up-regulation of these receptors or whether the up-regulation of the chemokine receptors causes modulated processing of APP. In the current study, we demonstrate that treatment of the chemokine receptor CXCR2 with agonists leads to enhancement of Abeta production and treatment with antagonists or immunodepletion of CXCR2's endogenous agonists leads to Abeta inhibition. Further, we found that the inhibitory effect of the antagonist of CXCR2 on Abeta40 and Abeta42 is mediated via gamma-secretase, specifically through reduction in expression of presenilin (PS), one of the gamma-secretase components. Also, in vivo chronic treatment with a CXCR2 antagonist blocked Abeta40 and Abeta42 production. Using small interfering RNAs for CXCR2, we further showed that knockdown of CXCR2 in vitro accumulates gamma-secretase substrates C99 and C83 with reduced production of both Abeta40 and Abeta42. Taken together, these findings strongly suggest for the first time that up-regulation of the CXCR2 receptor can be the driving force in increased production of Abeta. Our findings unravel new mechanisms involving the CXCR2 receptor in the pathogenesis of AD and pose it as a potential target for developing novel therapeutics for intervention in this disease. Also, we propose here a new chemical series of interest that can serve as a prototype for drug development.

Topics: Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Cells, Cultured; Chemokine CXCL1; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; gamma-Aminobutyric Acid; Humans; Interleukin-8; Mice; Mice, Transgenic; Phenylurea Compounds; Presenilins; Receptors, Interleukin-8B; Recombinant Proteins; RNA, Small Interfering; Sulfonamides; Triglycerides

Serotonin 1A receptor (5-HT(1A)R) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson's disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT(1A)R stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT(1A)R stimulation on DA receptor-mediated behaviors. Male Sprague-Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH(2)O) or the 5-HT(1A)R agonist +/-8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg+benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT(1A)R stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT(1A)R and DA receptor interactions may contribute to the unique profile of 5-HT(1A)R agonists for the improvement of PD treatment.

Topics: Adrenergic Agents; Analysis of Variance; Animals; Behavior, Animal; Biogenic Monoamines; Chromatography, High Pressure Liquid; Disease Models, Animal; Dopamine Agents; Drug Interactions; Dyskinesias; gamma-Aminobutyric Acid; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine; Serotonin Receptor Agonists; Stereotyped Behavior; Triglycerides

Loss of descending serotonergic (5-HT) projections after spinal cord injury (SCI) contributes to motor deficits and upregulation of receptors on partially denervated serotonergic targets in the spinal cord. Serotonergic agonists acting on these upregulated receptors are potential therapeutic agents that could ameliorate motor deficits. However, modification of 5-HT receptors following complete spinal cord injury results in different effects by 5-HT2C receptor agonists and antagonists. For example, administration of 5-HT2C receptor agonists suppresses locomotor activity in normal animals, but enhances it in spinalized animals. In addition, administration of 5-HT2C receptor agonists does not induce activity-dependent hindlimb tremors in normal animals, but does induce them in spinalized animals. We therefore extended our previous work with the 5-HT2C receptor agonist 1-(m-chlorophenyl)-piperazine hydrochloride (mCPP), which enhances weight-supported stepping when administered to adult rats spinalized as neonates, to identify the optimal dose for improved weight-supported stepping with minimal side effects. In order to determine whether mCPP enhances weight-supported stepping after SCI is through activation of the 5-HT2C receptor, we performed the following experiments. We determined that stimulation of the 5-HT1A receptor did not contribute to this improvement in weight-support. We reversed the increase in mCPP-induced weight-supported stepping with SB 206,553, a 5-HT2C receptor antagonist. We also provide evidence for denervation-induced upregulation of 5-HT2C receptors in the injured spinal cord. Since mCPP does not have the behavioral toxicity associated with non-selective 5-HT2 receptor agonists, targeting the 5-HT2C receptor may have clinical relevance for the treatment of SCI.

Topics: Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Exercise Test; Female; gamma-Aminobutyric Acid; Indoles; Motor Activity; Piperazines; Psychomotor Performance; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord Injuries; Triglycerides; Up-Regulation; Weight-Bearing

Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cognition; Cognition Disorders; Conditioning, Psychological; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Endopeptidases; Enzyme Inhibitors; Fear; gamma-Aminobutyric Acid; Mice; Mice, Transgenic; Mutation; Phosphodiesterase Inhibitors; Rolipram; Triglycerides