Neuroprotective Effects of HDAC Inhibitor, Trichostatin A, In Intracerebroventricular Streptozotocin Induced Cognitive Deficits In Rats

Rajeev Taliyan, Sorabh Sharma. Birla Institute of Technology and Science, Pilani-333031, Rajasthan, India, Rajasthan, India

Recent studies have highlighted the pathological role of histone deacetylases (HDACs) in cognitive impairment. The present study was undertaken to determine the therapeutic potential of HDAC inhibitor, Trichostatin A (TSA) in Intracerebroventricular-Streptozotocin (ICV-STZ) induced sporadic Alzheimer's disease. Male Wistar rats (200-250g) were injected with STZ twice (3 mg/kg, ICV) on alternate days (day 1 and 3) using following coordinates: 0.8 mm posterior to bregma; 1.5 mm lateral to sagittal suture; 3.6 mm ventral from the surface of the brain [1]. The ICV-STZ treated rats received either vehicle (0.5% DMSO in saline) or TSA (0.5 and 1mg/kg, i.p.) for a period of 21 days. The results are expressed as mean ± S.D. (n=10). The data was analyzed by One-way ANOVA followed by Tukey's post hoc tests or by Two way ANOVA followed by bonferroni post hoc test, using statistical GraphPad Prism software. P < 0.05 was set to be statistically significant. The ICV-STZ administration results in significant memory impairment, reduced level of brain derived neurotrophic factor (BDNF), the increased oxidative-nitrosative stress, acetylcholinesterase (AChE) activity and neuro-inflammation. Using behavioural tests, we observed that TSA treatment dose dependently improved the spatial learning and memory impairments (morris water maze)(Fig.1a, P<0.05). TSA treatment significantly attenuates the oxido-nitrosativeative stress markers, AChE activity and neuroinflammation as compared to untreated ICV-STZ rats (Table-1). Further, TSA treatment also augments the BDNF levels as compared to untreated ICV-STZ rats (Fig.1b,P<0.05). Based upon these findings, it could be suggested that HDAC inhibition could prove to be beneficial in ICV-STZ induced cognitive deficit and this neuroprotection could be the result of enhanced BDNF based synaptic plasticity as a result of increased histone acetylation.

Reference

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