During the last review period, we have shown that the brain DHA status can positively affect the behavioral and histologic outcome in a clinically relevant head injury model using the repetitive Closed-Head Impact Model of Engineered Rotational Acceleration (rCHIMERA). As the DHA status is closely linked to synaptamide production, observed neuroprotective effects of DHA may be contributed by synaptamides biological effects. During this review period, we tested the neuroprotective effect of synaptamide using rCHIMERA injury model in 12-week old C57BL/6 wild-type (WT) and GPR110 knock-out (GPR110 KO) mice. We found that intraperitoneal injection of synaptamide (5 mg/kg) immediately after each CHIMERA impact, significantly reduced glia cell activation in corpus callosum, CA1 and optic tract from day 1 to 3.5 months post injury and significantly improved the rCHIMERA-induced spatial memory deficit at 2 months in wild-type but not in GPR110 KO mice. These data suggest that beneficial effects of raising the brain DHA level on TBI outcome may at least partly be derived from its metabolism to synaptamide which exerts neuroprotective bioactivity through GPR110 activation. As visual dysfunction is a common occurrence after TBI, we investigated during this period whether vision is affected by varying degrees of head injury using a single or three mild CHIMERA (rCHIMERA) in relation to histologic outcome. The mice with multiple head injuries showed impaired performance in the visible platform water maze test and increased errors in the visual cliff test while single injury did not produce similar deficits. The visual evoked potential (VEP) indicated a graded difference with the single injury mice showing modest reduction in the N1 amplitude while the multiple injury produced significant reduction compared to sham. The optic tract of the injured mice showed increases in glial cell immunostaining. The increase in GFAP immunostaining reached statistical significance for both injured optic tracts while the Iba-1 immunostaining was only significantly increased in the repeatedly injured group. These results indicate that multiple injuries using CHIMERA may result in visual deficits. The change in vision, particularly VEP, can be used as a convenient functional marker to monitor injury outcome or to screen for therapeutic agents for TBI. The GPR110-dependent in vivo effect of synaptamide demonstrated by the suppression of immunohistochemical responses for GFAP and Iba-1, as well as spatial memory improvement suggests the potential therapeutic effects of synaptamide also on vision after TBI. Indeed, preliminary results obtained with one-time intravitreal injection of synaptamide (2.5 mg/kg) following the last injury showed significant improvement in VEP function measured at 2 weeks after injury.
|Chen, Huazhen; Desai, Abhishek; Kim, Hee-Yong (2017) Repetitive Closed-Head Impact Model of Engineered Rotational Acceleration Induces Long-Term Cognitive Impairments with Persistent Astrogliosis and Microgliosis in Mice. J Neurotrauma 34:2291-2302|
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