Neuroprotective effect of cyclosporine and FK506 against 3-nitropropionic acid induced cognitive dysfunction and glutathione redox in rat: possible role of nitric oxide.
Cyclosporine and FK506, a well-known immunosuppressant drugs that are presently being used for prevention of allograft rejection. Recently, several studies suggest their therapeutic potential in the treatment of neurodegenerative diseases. Therefore, present study was conducted to explore their therapeutic potential against 3-nitropropionic acid induced cognitive dysfunctions and biochemical alterations in striatum, cortex and hippocampal regions of brain. Further, attempt has also been made to investigate their possible interaction with nitric oxide modulators.3-Nitropropionic acid (10 mg/kg) for 14 days treatment significantly impaired cognitive task as evidenced by Morris water as well as plus maze performance tasks. 3-Nitropropionic acid treatment significantly disturbed glutathione redox ratio and different levels of glutathione (as indicated by alterations in total glutathione, reduced glutathione, oxidized glutathione, glutathione-S-transferase levels). Acetylcholinesterase enzyme activity was also significantly disturbed by 3-NP treatment. Further, FK-506 (0.5, 1 and 2 mg/kg, p.o.) and cyclosporine (2.5, 5 and 10 mg/kg, p.o.) treatment significantly improved cognitive functions both in Morris water maze and plus maze tasks. Beside these drug treatment significantly attenuated oxidative stress as evidenced by restoring different glutathione levels and acetylcholinesterase activity as compared to control (3-NP treated) animals. Further sub effective doses of cyclosporine (5 mg/kg) and FK-506 (1 mg/kg) effect was potentated by l-NAME and reversed by l-arginine pretreatment. The effects were significant as compared to their effect per se.Study highlights the therapeutic potential of these drugs in the treatment of Huntington's disease. Study further suggest that nitric oxide modulation in involved in the neuroprotective effect of these drugs against 3-NP neurotoxicity.
Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India.
Puneet
P
Kumar
Anil
A
Kumar
D000110:Acetylcholinesterase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D005982:Glutathione Transferase; D000110:Acetylcholinesterase; D005978:Glutathione; C015392:3-nitropropionic acid; D019331:NG-Nitroarginine Methyl Ester; D016559:Tacrolimus