This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.
In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.
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