Across almost all types of neurological pathophysiology, inflammation and corresponding breakdown of the Blood Brain Barrier (BBB) are hallmarks of injury/disease progression. In fact, BBB disruption can occur early during neuropathophysiological development, in many cases even before neurological and cognitive impairments become apparent. Whether as an early causative factor, a side effect, or both as it pertains to neurological injury/disease, BBB breakdown and dysfunction represents a novel and under investigated target for therapeutic development, especially for neurological pathologies with unmet therapeutic needs. Toward this goal, the endocannabinoid system (ECS) has emerged as a promising biological target for drug discovery efforts. Particularly, the Cannabinoid 2 Receptor (CB2R) has been proposed as a druggable target due to its anti-inflammatory effects and since it is not associated with the neurological side effect profile representative of Cannabinoid 1 Receptor (CB1R) drugs. Interestingly, neuroinflammatory conditions promote upregulation of CB2R on brain microvascular endothelial cells (BMVECs) suggesting a possible role toward resolution of inflammation in this cell type. Moreover, previous research has shown promising effects of CB2R agonists on cerebrovascular function, although these effects cannot be directly attributed to endothelial CB2R. The central hypothesis of this research is that endothelial CB2R activation confers effects which are vascular protective and that promote BBB repair, (irrespective of the effects of CB2R in other central nervous system (CNS) cell types). To address this hypothesis, endothelial CB2R expression dynamics were assessed following experimental Traumatic Brain Injury (TBI) followed by a series of assays to assess the therapeutic potential of a novel chromenopyrazole based CB2R agonist, PM289. Results of these experiments demonstrated upregulation of CNR2, the gene which encodes CB2R, following in vivo experimental TBI and in vitro cytokine induced inflammation. Moreover, PM289 exhibited robust CB2R-dependent therapeutic potential by partially restoring TNFa-induced physical barrier disruption, attenuating TNFa-induced ICAM1 upregulation, and promoting rapid monolayer repair following electrolytic wound. Mechanistically, these effects may be explained via CB2R-dependent inhibition of NFkB/P65 signaling. Overall, these results are supportive of the notion that CB2R in BMVECs could aid in vascular protection and promote BBB function in the context of neuroinflammation. Future studies are warranted to understand the in vivo therapeutic efficacy of PM289 in a variety of injury/disease models. Additionally, alternative cell signaling mechanisms should be considered including a comprehensive examination of potential interplay between ECS components and candidates that fall under the umbrella of the endocannabionoidome (ECBome). / Biomedical Sciences

Le virus de l'herpès simplex de sérotype 1 (HSV-1) est la plus grande cause de l’aveuglement infectieuse dans les pays développés. Les infections cornéennes à HSV-1 ont plusieurs conséquences, comme la difficulté à éliminer l'infection virale et l'inflammation provoquant une plus grande opacité de la cornée. Une infection cornéenne a montré qu'il y a colocalisation des cellules souches et les cellules amplificatrices transitoires avec le virus, mais le HSV-1 était toujours abondant dans le limbe de l'œil. Pour combattre le virus, anciennes publications ont montré que LL37, une cathélicidine humaine, peut réduire la charge virale. Le GF19, un fragment de LL37 modifié pour favoriser la perméabilité, a été capable de réduire la charge virale in vitro et ex vivo, avec la possibilité d'avoir des effets thérapeutique et préventif. Pour combattre les conséquences inflammatoires, un agoniste cannabinoïde CB2r impliqué dans la modulation de la neuroinflammation, TA-A001, a été testé. Des souris ayant reçu des brûlures alcalines pour induire l’inflammation et ils ont montré de meilleurs résultats cliniques avec le TA-A001 qu'avec le véhicule du médicament seul ou un corticostéroïde, la prednisolone. En conclusion, il apparaît que l’HSV-1 infecte rapidement le limbe, que le GF19 a pu réduire la charge virale, et que le TA-A001 a pu réduire l'inflammation en ayant peu d'effets secondaires. Une combinaison des traitements antiviraux et immunosuppresseurs administrés à la cornée pourrait être examinée plus pour combattre contre les infections à HSV-1 dans les yeux. / Herpes Simplex Virus serotype 1 (HSV-1) is the most common cause of infectious blindness in developed countries. Little is known about the early events in HSV-1 ocular infections since clinical symptoms often appear a week after infection. There are two significant consequences of HSV-1 corneal infection: the viral impacts of the disease and the inflammatory impacts. In mouse corneas, after HSV-1 infection, viruses localized in the limbal area of the cornea. However, there was no/little immunohistochemical co-localization with the stem cells or transient amplifying cells. Previous work has shown that LL37, a human cathelicidin, can reduce the viral burden. GF19, a fragment of LL37 with a modification to promote permeability, reduced viral loads in vitro and in ex vivo corneas. To combat the inflammatory consequences of HSV-1 infection, a cannabinoid CB2r agonist implicated in neuroinflammation modulation, TA-A001, was tested. Mice given alkali burns to induce inflammation showed better clinical results with TA-A001 than with the drug’s vehicle alone or a corticosteroid, prednisolone. In conclusion, it appears that HSV-1 quickly infects the limbus, GF19 was able to reduce viral burden, and CB2 agonists such as TA-A001 could reduce inflammation with few side effects. A combination of the anti-viral and immunosuppressant treatments could be a potential HSV-1 treatment.