Both clinical and experimental studies have suggested that inflammation is a key player in the progression of traumatic brain injury (TBI)-associated pathologies and neural repair. Uncontrolled inflammation can lead to exacerbated tissue damage and can hinder the repair process. While the role of local inflammation originating in the injured brain has been examined in some detail, the contribution of systemic inflammation to TBI outcome is less established. It has been demonstrated that systemic inflammation is mediated, in large part, by the spleen, which is regulated by the efferent component of the vagus nerve. Previous studies have shown that stimulation of the vagus nerve can reduce BBB permeability, cerebral edema and improve learning after TBI, suggesting a role for systemic inflammation in TBI outcome. However, the mechanism(s) by which vagus nerve activity exerts these effects is not understood. Recent studies have shown that this effect requires splenic nicotinic alpha 7 nicotinic acetylcholine receptor (alpha7nAChR). We propose to test the hypothesis that loss of alpha 7 nicotinic cholinergic signaling worsens, while augmentation of alpha7nAChR signaling improves, inflammation, blood-brain barrier (BBB) integrity and cognitive outcome.
Three Specific Aims are outlined to test our hypothesis.
Aim1 : To examine if alpha7nAChRs regulate TBI-associated inflammation.
Aim 2 : To test if alpha7nAChR signaling regulates BBB permeability and cerebral edema following TBI.
Aim 3 : To determine if post-TBI administration of alpha7nAChR agonists improves learning and memory and offers neuroprotection. The results from these studies will not only test a novel mechanism underlying TBI pathology, but will test the therapeutic potential of mechanism-based agents as a treatment for TBI.
Traumatic brain injury (TBI) remains a public health concern, the consequences of which can lead to long-lasting disability. Uncontrolled inflammation, which can occur after TBI, profoundly influences neuronal survival and outcome. The present proposal will investigate if modulating the function of nicotinic alpha7acetocholine receptors can reduce BBB permeability and improve cognitive function after TBI.
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| Dash, Pramod K; Zhao, Jing; Kobori, Nobuhide et al. (2016) Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood-Brain Barrier Permeability following Experimental Traumatic Brain Injury. J Neurosci 36:2809-18 |
