Brain-derived neurotrophic factor rescues neuronal death induced by methamphetamine.
BACKGROUND
Methamphetamine (MA) induces degeneration of various regions of the brain, resulting in neuropsychiatric damage. Although the underlying mechanisms of MA-induced neurotoxicity have been studied, there are few reports to date regarding the factor(s) that can effectively prevent MA-induced neurotoxicity. Because brain-derived neurotrophic factor (BDNF) has been known to prevent many kinds of neuronal cell death, we investigated whether BDNF inhibits MA-induced neuronal death.


METHODS
Using primary cortical neurons, we examined the effect of BDNF on MA-induced neuronal death. In addition, using pharmacologic and molecular biological tools, we elucidated which pathways are involved in this effect.


RESULTS
Brain-derived neurotrophic factor dose-dependently blocked MA-induced neuronal death, and this effect was inhibited by phosphatidylinositol-3-kinase inhibitors. In addition, overexpression of activated Akt protects neurons against MA. Furthermore, expression of kinase-defective Akt blocked the effect of BDNF on MA-induced neuronal death.


CONCLUSIONS
Brain-derived neurotrophic factor effectively blocks MA-induced neuronal death, and Akt activation is necessary and sufficient for this effect.
Matsuzaki
Hideo
H
Department of Anatomy, Hamamatsu University School of Medicine, Shizuoka, Japan.
Namikawa
Kazuhiko
K
Kiyama
Hiroshi
H
Mori
Norio
N
Sato
Kohji
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors / Q000235:genetics; D008694:Methamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar
D019208:Brain-Derived Neurotrophic Factor; D053148:Caspase 3; D020169:Caspases; D000697:Central Nervous System Stimulants; D004274:DNA, Recombinant; D004279:DNA, Viral; D008694:Methamphetamine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494920:Akt1 protein, rat; C505410:Casp3 protein, rat