Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.
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.
Lauterbach
Edward C
EC
Mercer University Center for Translational Studies in Alzheimer's, Parkinson's, and Neurodegenerative Diseases, Macon, GA 31201, USA. eclbgnp@earthlink.net
Victoroff
Jeff
J
Coburn
Kerry L
KL
Shillcutt
Samuel D
SD
Doonan
Suzanne M
SM
Mendez
Mario F
MF
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000975:Antioxidants / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D002998:Clonazepam / Q000494:pharmacology / Q000627:therapeutic use; D003891:Desipramine / Q000494:pharmacology / Q000627:therapeutic use; D003987:Dibenzothiazepines / Q000494:pharmacology / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016651:Lithium Carbonate / Q000494:pharmacology / Q000627:therapeutic use; D008376:Maprotiline / Q000494:pharmacology / Q000627:therapeutic use; D008550:Melatonin / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000077152:Olanzapine; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D000077487:Pramipexole; D000069348:Quetiapine Fumarate; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D052160:Benzothiazoles; D002998:Clonazepam; D003891:Desipramine; D003987:Dibenzothiazepines; D018491:Dopamine Agonists; D016651:Lithium Carbonate; D008376:Maprotiline; D008550:Melatonin; D018696:Neuroprotective Agents; D000077152:Olanzapine; D000077487:Pramipexole; D000069348:Quetiapine Fumarate; D017367:Selective Serotonin Reuptake Inhibitors; D014635:Valproic Acid