Effects of alpha-lipoic acid in an animal model of mania induced by D-amphetamine.
OBJECTIVE
Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania.


METHODS
In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC.


RESULTS
ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. PREVENTION MODEL: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. REVERSAL MODEL: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC.


CONCLUSIONS
Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect.
Neuropharmacology Laboratory, Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
Danielle S
DS
Macêdo
Camila D
CD
Medeiros
Rafaela C
RC
Cordeiro
Francisca Cléa
FC
Sousa
Júnia V
JV
Santos
Thomás A
TA
Morais
Thomas N
TN
Hyphantis
Roger S
RS
McIntyre
João
J
Quevedo
André F
AF
Carvalho
D000818:Animals; D018692:Antimanic Agents / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D003913:Dextroamphetamine / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D018021:Lithium Chloride / Q000097:blood / Q000627:therapeutic use; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D008063:Thioctic Acid / Q000627:therapeutic use*
D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; D000697:Central Nervous System Stimulants; D017392:Thiobarbituric Acid Reactive Substances; D008315:Malondialdehyde; D008063:Thioctic Acid; D013482:Superoxide Dismutase; D018021:Lithium Chloride; D005978:Glutathione; D003913:Dextroamphetamine