Modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum.
Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 × 5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2 × 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.
Instituto de Investigaciones Farmacológicas (Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Técnicas), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
Mariana
M
Raineri
Betina
B
Gonzalez
Belen
B
Goitia
Edgar
E
Garcia-Rill
Irina N
IN
Krasnova
Jean Lud
JL
Cadet
Francisco J
FJ
Urbano
Veronica
V
Bisagno
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005334:Fever / Q000517:prevention & control; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000077408:Modafinil; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D000077408:Modafinil