Abstract
Rationale and Objectives
5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes.
Methods
In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3 mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14 days from the first day of ICV-STZ.
Results
Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5 mg/kg) and antagonist SB-399885 (10 mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible.
Conclusion
The findings in this study support the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.
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The authors express their gratitude to Lupin Ltd., Lupin Research Park, Pune and Manipal University, Manipal for their support and help.
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Experiments were performed according to internationally followed ethical standards and approved by the research ethics committee of Lupin Ltd. (Lupin Research Park) framed as per the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), India.
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Bokare, A.M., Bhonde, M., Goel, R. et al. 5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats. Psychopharmacology 235, 1557–1570 (2018). https://doi.org/10.1007/s00213-018-4866-z
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DOI: https://doi.org/10.1007/s00213-018-4866-z