Abstract

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.