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Synergistic effects of GSK-3β and HDAC inhibitors in intracerebroventricular streptozotocin-induced cognitive deficits in rats

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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.

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Acknowledgments

The authors are thankful to University Grants Commission (UGC), New Delhi, India, and BITS, Pilani, India, for their financial support for this study. The authors are highly thankful to Dr. B. Pal (anesthesiologist) (Birla Saravajanik Hospital, Pilani) for his support and guidance during anesthesia of animals.

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  1. Department of Pharmacy, Birla Institute of Technology and Science, Pilani, 333031, Rajasthan, India

    Sorabh Sharma & Rajeev Taliyan

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Sharma, S., Taliyan, R. Synergistic effects of GSK-3β and HDAC inhibitors in intracerebroventricular streptozotocin-induced cognitive deficits in rats. Naunyn-Schmiedeberg's Arch Pharmacol 388, 337–349 (2015). https://doi.org/10.1007/s00210-014-1081-2

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