Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis.
We investigated whether certain hydrophobic dipeptides, Leu-Ile, Leu-Pro, and Pro-Ile, which partially resemble the site on FK506 that binds to immunophilin, could stimulate glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) synthesis in cultured neurons and found only Leu-Ile to be an active dipeptide. Leu-Ile protected against the death of mesencephalic neurons from wild-type mice but not from mice lacking the BDNF or GDNF gene. Next, we examined the effects of i.p. or i.c.v. administration of Leu-Ile on BDNF and GDNF contents. Both types of administration increased the contents of BDNF and GDNF in the striatum of mice. Also, peripheral administration of Leu-Ile inhibited dopaminergic (DA) denervation caused by unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of mice. The number of rotations following a methamphetamine challenge was lower in the Leu-Ile-treated group than in the nontreated group. Next, we compared the calcineurin activity and immunosuppressant activity of Leu-Ile with those of FK506. Leu-Ile was not inhibitory toward calcineurin cellular activity in cultured neuronal cells. Furthermore, Leu-Ile did not suppress concanavalin A (ConA)-induced synthesis/secretion of interleukin-2 by cultured spleen cells, suggesting that the immunosuppressant activity of Leu-Ile may be negligible when used as a therapeutic tool for neurodegenerative diseases.
Nitta
Atsumi
A
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan. a-nitta@med.nagoya-u.ac.jp
Nishioka
Hirofumi
H
Fukumitsu
Hidefumi
H
Furukawa
Yoshiko
Y
Sugiura
Haruo
H
Shen
Liya
L
Furukawa
Shoei
S
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D065095:Calcineurin Inhibitors; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D004298:Dopamine / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006624:Hippocampus / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007376:Interleukin-2 / Q000096:biosynthesis; D008636:Mesencephalon / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D065095:Calcineurin Inhibitors; D004151:Dipeptides; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C492946:leucyl-isoleucyl; D016627:Oxidopamine; D004298:Dopamine