PubMed · 92463
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H Wekerle. 1979. [Autoreactivity and autoaggression].. https://pubmed.ncbi.nlm.nih.gov/92463/
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Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.
The widespread use of organophosphorus compounds (OP) as pesticides and the repeated misuse of highly toxic OP as chemical warfare agents (nerve agents) emphasize the necessity for the development of effective medical countermeasures. Standard treatment with atropine and the established acetylcholinesterase (AChE) reactivators, obidoxime and pralidoxime, is considered to be ineffective with certain nerve agents due to low oxime effectiveness. From obvious ethical reasons only animal experiments can be used to evaluate new oximes as nerve agent antidotes. However, the extrapolation of data from animal to humans is hampered by marked species differences. Since reactivation of OP-inhibited AChE is considered to be the main mechanism of action of oximes, human erythrocyte AChE can be exploited to test the efficacy of new oximes. By combining enzyme kinetics (inhibition, reactivation, aging) with OP toxicokinetics and oxime pharmacokinetics a dynamic in vitro model was developed which allows the calculation of AChE activities at different scenarios. This model was validated with data from pesticide-poisoned patients and simulations were performed for intravenous and percutaneous nerve agent exposure and intramuscular oxime treatment using published data. The model presented may serve as a tool for defining effective oxime concentrations and for optimizing oxime treatment. In addition, this model can be useful for the development of meaningful therapeutic animal models.
RATIONALE: The role of the hippocampal dopaminergic system in mnemonic function has not been clarified yet. OBJECTIVE: We previously reported that the dopamine D2 receptor (D2R) is involved in the regulation of acethylcholin (ACh) release in the hippocampus. In this study, we further investigated ACh-dopamine (DA) interaction in the hippocampus and its involvement in mnemonic function. METHODS: For experiment 1, rats fed with Cholin (Ch)-deficient chow were used. We examined the effects of D2R antagonist, raclopride, on cognitive performance using a passive avoidance task. We further carried out in vivo microdialysis to assess the effect of infusion of D2R agonist, quinpirole, into the ventral hippocampus on its capacity to release ACh. For experiment 2, rats fed with normal chow were used. The performance of a radial arm maze task was assessed to examine the effects of hippocampal injection of D2R agonist, quinpirole, on memory impairment induced by scopolamine, a muscarinic ACh antagonist. RESULTS: In experiment 1, rats fed with Ch-deficient chow showed impaired performances indicated by prolonged latency on retention trials of a passive avoidance task following the hippocampal injection of D2R antagonist, and showed reduced capacity to release ACh following the injection of D2R agonist compared with rats fed with normal chow. In experiment 2, memory impairment induced by the intraperitoneal injection of scopolamine was ameliorated by the injection of D2R agonist into the ventral hippocampus. CONCLUSION: These results indicate the possible involvement of hippocampal ACh-DA interaction in mnemonic processing.