Prostaglandin F2α FP receptor antagonist improves outcomes after experimental traumatic brain injury

Abstract

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.

Deficiency of complement receptors CR2/CR1 in Cr2 -/-mice reduces the extent of secondary brain damage after closed head injury

“…Similarly, the underlying root cause of the impressive attenuation of the extent of post-injury glial activation observed in head-injured Cr2 -/- mice in this study (Figure  5) remains a topic of speculation. Recent studies have emphasized an important role for activated microglia and reactive astrocytosis in contributing to post-injury neuroinflammation and adverse outcomes [34-36]. A recently published experimental study using the controlled cortical impact (CCI) model in Wistar rats revealed that microglial activation after focal TBI peaked within the first three to seven days post injury which reflects a similar timeline of cellular activation observed in the present study [34].…”

Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury

“…In addition, EP1 −/− mice have enhanced cerebral blood flow at reperfusion in a ischemic stroke model [34]. However, there are no significant morphological or anatomical differences in cerebrovascular vasculature between EP1 −/− and WT mice or between FP −/− and WT mice in our related studies [21], [34]. Vascular damage plays an important role in TBI and is a primary cause of ICH, which correlates with TBI severity [61] and triggers secondary biochemical cascades, exacerbating primary injury involving several events associated with disrupted Ca 2+ signaling such as extensive glutamate release and calpain-dependent cortical necrosis [61]–[64].…”

“…However, our most recent data documented that systemic administration of a selective FP receptor antagonist significantly improved anatomical and functional outcomes in various brain injury models, both in vivo and in vitro, including ischemic stroke, excitotoxicity, and TBI, and the selectivity of an FP antagonist was confirmed in genetic knockout mice lacking the FP receptor (FP −/− ) [17], [19]–[21], [23]. Based on the data from our group and others, the roles of prostaglandin receptors are complex and the outcomes of inhibition or genetic deletion of some of these receptors, such as EP1, may have the opposite effects in different neurological conditions such as ischemic and hemorrhagic strokes [19], [22]–[24].…”

“…Various biological actions of the specific prostaglandins are mediated via activation of several different isotypes of their cognate membrane G-protein-coupled receptors (GPCRs), and thus far the data suggest that the prostaglandin receptors, which exert most of their action through activation of intracellular calcium (Ca 2+ )-signaling, such as closely related PGE 2 receptor EP1 and PGF 2α receptor FP [11], [17]–[19], exacerbate neuronal dysfunction after ischemic and excitotoxic brain injuries [11], [17], [19]–[23]. Previous data indicates that genetic deletion or pharmacological blockade of functionally related FP receptor with Ca 2+ -signaling mechanisms [17], [18] is beneficial in stroke [17], [20] and TBI [21], which are consistent with the generally recognized notion that overactivation of the FP receptor in a disease state, with a few exceptions, is deleterious [10]. Nevertheless, based on our recent data obtained using a model of intracerebral hemorrhage (ICH) [24], the roles of prostaglandin receptors are complex and the outcomes of inhibition or genetic deletion of some of these receptors, such as EP1, may have opposing effects in different neurological conditions, such as ischemic and hemorrhagic strokes [19], [22]–[24].…”

Optimization of a Clinically Relevant Model of White Matter Stroke in Mice: Histological and Functional Evidences

“…This task was designed to assess neuromuscular function and muscular strength by sensing the maximal peak force of the mouse forelimb [32–34]. Muscle strength was measured using a Grip Strength Meter (San Diego instruments Inc., San Diego, CA).…”