5-Hydroxytryptamine receptor 6 antagonist, SB258585 exerts neuroprotection in a rat model of Streptozotocin-induced Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline. It has been suggested that 5-hydroxytryptamine receptor 6 (5-HT6R) might be involved in AD pathology. The aim of this study was to evaluate the effect of a 5-HT6R antagonist on cognition, learning, memory, and hippocampal apoptosis in an experimental rat model of AD. AD was induced by intracerebroventricular (icv) administration of streptozotocin (STZ; 3 mg/kg, 10 μL, twice). Adult, male rats were divided into the following groups: control, sham, AD (saline treatment, 1 μL icv for 30 days), and AD + SB258585 (5-HT6R antagonist, 1 μg/μL icv for 30 days). Following the treatment period, novel object recognition (NOR) and passive avoidance learning (PAL) tests were conducted to measure cognition, as well as learning and memory, respectively. TUNEL staining was used to evaluate apoptosis in the hippocampus. This study demonstrates that icv STZ injections induce apoptosis in hippocampal cells, decrease the NOR discrimination index, increase the number of trials needed to reach acquisition and the time spent in the dark compartment during PAL, as compared with sham and control groups. Subsequent administration of SB258585 in the STZ treated rats increased the NOR discrimination index, decreased the number of trials till acquisition and the time spent in the dark compartment during PAL, while decreasing neuronal apoptosis, as compared to the untreated AD group. Thus, we conclude that long-term administration of the 5-HT6R antagonist SB258585, ameliorates AD-associated cognitive and behavioral impairments through the suppression of apoptosis in the hippocampus.