title: Synergistic effects of GSK-3β and HDAC inhibitors in intracerebroventricular streptozotocin-induced cognitive deficits in rats.
abstract: Recent studies suggest the importance of combined treatment of glycogen synthase kinase-3β (GSK-3β) and histone deacetylase (HDAC) inhibition in various in vitro and in vivo models of neurological diseases. Lithium chloride (LiCl) and valproate (VPA), two well-known mood stabilizers, have been reported to act through GSK-3β and HDAC inhibition, respectively. The present study was designed to investigate the potential of low-dose combination of LiCl and VPA in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficits in rats. STZ was injected twice (3 mg/kg ICV) on alternate days (day 1 and day 3) in rats. The ICV-STZ-treated rats received LiCl (60 mg/kg, i.p.), VPA (200 mg/kg, i.p.), and combination of both LiCl (60 mg/kg, i.p.) and VPA (200 mg/kg, i.p.) drugs for a period of 3 weeks. The ICV-STZ administration results in significant memory impairment, elevated oxidative-nitrosative stress, and reduced brain-derived neurotrophic factor (BDNF) levels. Using a battery of behavioral and biochemical tests, we observed that co-treatment of both drugs showed synergistic effect in improving the spatial learning and memory impairment as well as significantly attenuated the oxidative stress markers in STZ-treated rats as compared to either drug alone. Moreover, the combination of both drugs reversed the hyperinsulinemic brain condition and improved the BDNF levels in STZ-treated rats. Based upon these results, it could be suggested that a low-dose combination of LiCl and VPA produces synergistic and more consistent neuroprotective effects in ICV-STZ-induced cognitive deficits in rats.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, 333031, Rajasthan, India.
authors.forename: Sorabh
authors.initials: S
authors.lastname: Sharma
authors.forename: Rajeev
authors.initials: R
authors.lastname: Taliyan
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D018021:Lithium Chloride / Q000627:therapeutic use*; D008315:Malondialdehyde / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D017208:Rats, Wistar; D065853:Spatial Learning / Q000187:drug effects; D013311:Streptozocin; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D007328:Insulin; D018696:Neuroprotective Agents; D009566:Nitrates; D009573:Nitrites; D008315:Malondialdehyde; D013311:Streptozocin; D014635:Valproic Acid; D038362:Glycogen Synthase Kinase 3; D000110:Acetylcholinesterase; D018021:Lithium Chloride; D005978:Glutathione