A 5-HT₆R agonist alleviates cognitive dysfunction after traumatic brain injury in rats by increasing BDNF expression

Area of Science:

• Neuroscience
• Pharmacology
• Traumatic Brain Injury Research

Background:

• Cognitive dysfunction following traumatic brain injury (TBI) lacks effective clinical treatments.
• Brain-derived neurotrophic factor (BDNF) is crucial for cognitive function, and its upregulation can mitigate TBI-induced cognitive deficits.
• Selective 5-hydroxytryptamine receptor 6 (5-HT₆R) agonists have shown potential in increasing BDNF expression and improving cognition.

Purpose of the Study:

• To evaluate the neuroprotective effect of the selective 5-HT₆R agonist WAY-181187 on cognitive dysfunction after experimental TBI.
• To investigate the impact of WAY-181187 on BDNF expression and neuronal structural plasticity in TBI models.

Main Methods:

• A controlled cortical impact model of moderate TBI was established in rats.
• WAY-181187 (3 mg/kg) was administered daily for five consecutive days post-TBI.
• Cognitive function was assessed using the Morris water maze, and BDNF levels, dendritic spine density, and morphology were analyzed in the medial prefrontal cortex (mPFC) and hippocampus.

Main Results:

• TBI induced significant spatial reference memory impairment, reduced BDNF expression, and altered dendritic spine morphology (decreased density of thin/mushroom spines, increased stubby spines).
• WAY-181187 administration significantly alleviated cognitive dysfunction at one and four weeks post-TBI.
• Treatment upregulated BDNF expression in the mPFC and hippocampus and improved dendritic spine density and morphology at five weeks post-TBI.

Conclusions:

• WAY-181187 demonstrates significant efficacy in ameliorating cognitive dysfunction following TBI in a rat model.
• The therapeutic benefits of WAY-181187 appear to be mediated by the upregulation of BDNF and enhancement of neuroplasticity in key brain regions.
• This study supports WAY-181187 as a promising therapeutic agent for managing cognitive impairments after TBI.