The Protective Effect Of 5-HT6 R Agonists On Cognitive Impairment After Traumatic Brain Injury

BackgroundModerate to severe traumatic brain injury(TBI)causes long-term,persistent cognitive impairment.However,no effective treatment for cognitive dy sfunction following TBI is currently in clinical practice.Cognitive impairment following TBI was associated with increased extracellular glutamate levels,inflammatory damage,and reduced brain-derived neurotrophic factor(BDNF)and synapsin Ⅰexpression in the injured side of the medial prefrontal cortex(mPFC)and hippocampus during the acute phase.5-hydroxytryptamine receptor 6(5-HT6R)is highly expressed in both human and rat hippocampus and cortex.It could decrease the abnormal release of glutamate during stressful conditions in the cortex and hippocampus,reduce inflammatory damage,and considerably increase BDNF expression to improve cognition.Therefore,a 5-HT6 R agonist may have a protective effect on cognitive impairment following TBI by lowering the abnormal release of extracellular glutamate,decreasing inflammatory damage,upregulating the expression of BDNF and synapsin I in the injured side of the mPFC and hippocampus,and enhancing neuroplasticity.Objectives1.To investigate whether treatment using 5-HT6 R agonists(drug intervention)during the acute stage significantly reduces cognitive impairment after TBI.2.To determine wether the mechanisms of action involve lowering the abnormally elevated extracellular glutamate level in the acute phase following TBI,decreasing the inflammatory damage in the injured side of the mPFC and hippocampus,increasing the expression of BDNF and synapsin I in the injured side of the mPFC and hippocampus,and improving synaptic plasticity.Methods.1.We established a controlled cortical impact model of moderate TBI in rats and performed drug intervention with a highly selective 5-HT6R agonist,WAY-181187,at doses of 1 and 3 mg/kg for 5 consecutive days.2.We assessed the impairment of spatial reference and work memory in rats 1 and 4 weeks after TBI using Morris water maze and Y-maze tests.3.We measured the levels of glutamate in cerebrospinal fluid at 24 hours after TBI and detected the expression of glial fibrillary acidic protein(GFAP)in the injured side of the mPFC and hippocampus at 2 and 5 weeks after TBI by WB and immunofluorescence.4.We determined the protein expression of BDNF in the injured side of the mPFC and hippocampus at 2 and 5 weeks following TBI by WB and immunofluorescence.WB was also used to determine the protein expression of synapsin I in the injured side of the mPFC and hippocampus at 2 and 5 weeks following TBI.Golgi staining was performed to observe the dendritic spines of neurons in the injured side of the mPFC and hippocampus at 5 weeks after TBI.Results1.Rats showed spatial reference and work memory impairment in the Morris water maze and Ymaze 1 and 4 weeks after moderate TBI.2.The levels of glutamate in cerebrospinal fluid increased significantly at 24 hours after TBI,and the expression of GFAP in the injured side of the mPFC and hippocampus increased significantly at 2 and 5 weeks after TBI.3.The expression of BDNF and synapsin I in the injured side of the mPFC and hippocampus decreased 2 and 5 weeks after TBI.Additionally,5 weeks after TBI,there was a decrease in the density of neuronal dendritic spines and the proportion of thin,mushroom-shaped dendritic spines,whereas an increase was observed in the proportion of stubby-type dendritic spines.4.WAY-181187 administration(3 mg/kg)for 5 consecutive days after TBI significantly improved Spatial reference and work memory dysfunction at 1 and 4 weeks,decreased the levels of glutamate in cerebrospinal fluid at 24 hours after TBI,decreased GFAP expression in the mPFC and hippocampus at two and five weeks,upregulated BDNF and synapsin I expression in the mPFC and hippocampus at two and five weeks,and increased dendritic spine density and the proportions of thin mushroomshaped dendrites spines in the mPFC and hippocampus at five weeks after TBI.ConclusionsOur findings show that WAY-181187 administration(3 mg/kg)during the acute phase significantly alleviated spatial memory dysfunction following TBI,possibly by decreasing abnormally elevated extracellular glutamate levels,reducing inflammatory damage,increasing BDNF and synapsin I expression in the mPFC and hippocampus,and enhancing neuroplasticity.