Neuropharmacology
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Oxaliplatin, unlike other platinum anticancer agents, has only mild toxic effects on the hematopoietic, urinary and gastrointestinal systems. Its dose-limiting side effect is neurotoxicity that may evolve to a neuropathic syndrome which is difficult to treat. In this study we treated rats with oxaliplatin (2.4 mg/kg/day intraperitoneally, for 3 weeks), and observed that expression levels of the α7 nicotinic acetylcholine receptor (nAChR) subunit were dramatically decreased both in the peripheral and central nervous system. ⋯ Astrocyte density was enhanced by the agonist treatment in the spinal cord, thalamus and somatosensory area 1 as opposed to the effects of oxaliplatin treatment. (R)-ICH3 and PNU-282987 per se increased glial cell number in a region-specific manner. In summary, α7 nAChR is involved in oxaliplatin-dependent neuropathology and the agonists (R)-ICH3 and PNU-282987 reduce pain and protect nervous tissue with concomitant glial activation. Since glial cells play a role both in pain and in neuroprotection, an α7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.
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Conditioned place preference (CPP) is widely used to investigate the rewarding properties of cocaine. Various brain regions and neurotransmitters are involved in developing cocaine CPP. However, the contribution of cholinergic transmission in the ventral tegmental area (VTA) to cocaine CPP remains largely unexplored. ⋯ Additionally, intra-VTA injection of scopolamine or mecamylamine before cocaine conditioning also attenuated cocaine CPP, demonstrating the contribution of cholinergic transmission via muscarinic and nicotinic acetylcholine receptors in CPP acquisition. Furthermore, intra-VTA injection of scopolamine or mecamylamine immediately before the test attenuated cocaine CPP, indicating that cholinergic signaling is also associated with the expression of CPP. These results suggest that cholinergic transmission from the LDT to the VTA is critically involved in both acquiring and retrieving cocaine-associated memories in cocaine CPP.
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Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. ⋯ The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans.
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The increase in incidence and prevalence of neurodegenerative diseases highlights the need for a more comprehensive understanding of how food components may affect neural systems. In particular, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in memory and learning in both animals and humans. Our previous studies highlight the efficacy of flavonoids in reversing memory impairments in aged rats, yet little is known about the effects of these compounds in healthy animals, particularly with respect to the molecular mechanisms by which flavonoids might alter the underlying synaptic modifications responsible for behavioral changes. ⋯ We observed parallel increases in hippocampal NMDA receptors containing the NR2B subunit for both 8.7 mg/day (p < 0.05) and 17.4 mg/day (p < 0.001) doses, suggesting an enhancement of glutamate signaling following flavonoid intervention. This is further strengthened by the simultaneous modulation of hippocampal ERK/CREB/BDNF signaling and the activation of the Akt/mTOR/Arc pathway, which are crucial in inducing changes in the strength of hippocampal synaptic connections that underlie learning. Collectively, the present data supports a new role for PSA-NCAM and NMDA-NR2B receptor on flavonoid-induced improvements in learning and memory, contributing further to the growing body of evidence suggesting beneficial effects of flavonoids in cognition and brain health.
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Dopamine replacement with l-DOPA is the most effective therapy in Parkinson's disease. However, with chronic treatment, half of the patients develop an abnormal motor response including dyskinesias. The specific molecular mechanisms underlying dyskinesias are not fully understood. ⋯ Pharmacological experiments combining buspirone with 5HT1A and DRD3 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required, but not sufficient, for blocking dyskinesias. The correlation between pDARPP32 ratio and dyskinesias was significant but not strong, pointing to the involvement of convergent factors and signalling pathways. Our results suggest that in dyskinetic rats DRD3 striatal over-expression could be instrumental in the activation of DRD1-downstream signalling and demonstrate that the anti-dyskinetic effect of buspirone in this model is correlated with DRD1 pathway normalization.