We have studied the possible interaction between the cannabinoid receptor agonist CP 55,940 (1 and 50 μg/kg) and the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg) in the modulation of plus-maze and holeboard activity in Wistar adult male rats. In the plus-maze, the higher dose of CP 55,940 induced an anxiogenic-like effect, whereas the lower dose induced anxiolytic-like responses. The 5-HT1A antagonist, which was silent in this test, attenuated the anxiogenic, but not the anxiolytic, effect of CP 55,940. In the holeboard, the higher dose of CP 55,940 significantly decreased head-dipping duration, and WAY 100635, which did not affect exploratory head-dipping when administered alone, antagonized this effect. The administration of WAY 100635 significantly increased grooming behaviour, and this effect was inhibited by the two doses of CP 55,940, which did not exert any effect, per se, on this parameter. We provide the first evidence implicating 5-HT1A receptors in anxiety-related behavioural responses to a cannabinoid agonist.

So far, intravenous tissue-type plasminogen activator (tPA) and mechanical removal of arterial blood clot (thrombectomy) are the only available treatments for acute ischemic stroke. However, the short therapeutic window and the lack of specialized stroke unit care make the overall availability of both treatments limited. Additional agents to combine with tPA administration or thrombectomy to enhance efficacy and improve outcomes associated with stroke are needed. Stroke-induced inflammatory processes are a response to the tissue damage due to the absence of blood supply but have been proposed also as key contributors to all the stages of the ischemic stroke pathophysiology. Despite promising results in experimental studies, inflammation-modulating treatments have not yet been translated successfully into the clinical setting. This review will (a) describe the timing of the stroke immune pathophysiology; (b) detail the immune responses to stroke sift-through cell type; and (c) discuss the pitfalls on the translation from experimental studies to clinical trials testing the therapeutic pertinence of immune modulators.

In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.