Traumatic brain injury (TBI) causes long-term neuroinflammation characterized by microglial activation and leading to progressive neurodegeneration.  Our recent results show that the neuroinflammation process can be targeted as late as 1 month after experimental TBI in rodents and still result in significant attenuation of the progressive neurodegeneration.  This was accomplished using a novel strategy targeting the metabotropic glutamate receptor type 5 (mGluR5) in microglia.  Stimulation of mGluR5 results in significant inhibition of microglia activation, which represents a key pathway for modulation of microglia activation.  A series of mGluR5 PAMs have been designed using a combination of computer-aided drug design (CADD) and medicinal optimization.  The synthesized compounds were evaluated in multiple assays involving cell lines, primary neurons, and neuronal microglial co-cultures.  The optimal drug candidates were tested for their effectiveness in reducing lesion volume and neurological dysfunction in a mouse CCI model.

Centrally active positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGluR5) for traumatic brain injury (TBI)

246th National Meeting (2013)

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