BackgroundInjuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2α, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.MethodsAccordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.ResultsMorphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm3 and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.ConclusionThis study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.
Background: Stroke and traumatic brain injury (TBI) are ones of the leading causes of death and disability in the USA. Secondary brain injury following TBI shares common features with neuropathology of stroke including oxidative stress and neuroinflammation. Although potentially treatable secondary injuries play a key role in the neurological outcomes currently there is no effective treatment and discovery of new therapeutic targets remains critical. Primary injury to the brain promotes upregulation of prostaglandins, notably the proinflammatory PGF2a, and overactivation of its FP GPCR which could exacerbate brain damage. Thus, our study is focused on the investigation of the FP receptor as a target for novel neuroprotective drugs in preclinical animal models of stroke and TBI. Methods: We used FP receptor knockout male C57BL/6 mice and post-treatment with the selective FP antagonist AL-8810 (1 and 10mg/kg, IP) in permanent middle cerebral artery occlusion (pMCAO) and controlled cortical impact (CCI) models. Neurological impairments assessed at 24 and 48h after injury using tape removal reflex and neurological deficit score, and brain pathology was assessed at 48h using triphenyltetrazolium chloride or cresyl violet. Results: Genetic deletion of the FP receptor or its blockade with AL-8810 at both doses significantly reduced cortical infarct volume and tape removal reflex following pMCAO. In vehicle treated animals, CCI caused cortical lesion with relative volume of 20.5±1.0% and significant hippocampal swelling (146.5±7.4% of contralateral) as compared with sham (P<0.05, n=4). AL-8810 had no significant effect on cortical lesion suggesting irreversible effect of primary CCI injury. However, AL-8810 at both doses reduced CCI-induced hippocampal swelling to the levels not significantly different from the sham. In CCI model, post-treatment with AL-8810 at dose 10mg/kg significantly improved neurological deficit score at 24 and 48h after CCI (P<0.001 and P<0.01, n=9-10); whereas the effect of 1mg/kg dose was not significant. Conclusion: This study provided, for the first time, clarification on the respective role of calcium-modulating PGF2a FP receptor as a potential target for disease-modifying CNS drugs for treatment of stroke and TBI.
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