Down-regulation of brain-pancreas relative protein in diabetic rats and by high glucose in PC12 cells: prevention by calpain inhibitors.
Brain-pancreas relative protein (BPRP) is a novel protein that we found in our laboratory. Previously we demonstrated that it is involved in ischemia and depression. In light of the putative association between diabetes and clinical depression, and the selective expression of BPRP in brain and pancreas, the present study examined whether BPRP levels are affected by induction of diabetes by alloxan injection in rats and exposure to high glucose levels in PC12 cells. Western blot and immunohistochemical analyses revealed that BPRP levels were decreased in the hippocampal CA1 neurons of diabetic rats 4 and 8 weeks post-alloxan injection and in PC12 cells 48 h after exposure to high concentrations of glucose. BPRP protein levels were not affected by osmolarity control treatments with mannitol. Follow-up pharmacological experiments in PC12 cells revealed that glucose-induced BPRP down-regulation was markedly attenuated by the calpain inhibitors N-acetyl-Leu-Leu-norleucinal (ALLN) or calpeptin, but not the proteasome-specific inhibitor carbobenzoxy-Leu-Leu-leucinal (MG132). The ability of calpain inhibitors to specifically counter the effects of high glucose exposure on BPRP levels further suggests that BPRP and calpain activity may contribute to diabetes complications in the central nervous system.
Tie
Lu
L
Department of Pharmacology, School of Basic Medical Sciences and State Key Laboratory of Natural & Biomimetic Drugs, Peking University, Beijing, China.
Xu
Ying
Y
Lin
Yan-Hua
YH
Yao
Xiao-Hao
XH
Wu
Hong-Li
HL
Li
Yu-Hua
YH
Shen
Zhu-Fang
ZF
Yu
He-Ming
HM
Li
Xue-Jun
XJ
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism*; D006207:Half-Life; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007328:Insulin; D007976:Leupeptins; D009419:Nerve Tissue Proteins; C516848:brain-pancreas relative protein, rat; C063261:acetylleucyl-leucyl-norleucinal; C071482:calpeptin; D002154:Calpain; D005947:Glucose; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde