Cannabidiol (CBD) as a Potential Therapeutic for Experimental Subarachnoid Hemorrhage

ABSTRACT Subarachnoid hemorrhage (SAH), commonly caused by a ruptured aneurysm, carries a high rate of disability and death. Preclinical studies demonstrate SAH induces morphological and functional changes in the cerebrovasculature, which contributes to early brain injury and delayed cerebral ischemia. Few treatment options currently exist for SAH patients, making it imperative to identify novel therapies to improve outcomes following SAH. Cannabidiol (CBD) has gained attention for its potential therapeutic properties and widespread mechanistic actions. First utilized for the treatment of pain, preclinical studies demonstrate CBD has anti-inflammatory, neuroprotective, and vascular stabilization properties in experimental models of injury. However, understanding of the effects of CBD on the cerebrovasculature is limited, and no studies have directly investigated CBD as a treatment for SAH, representing critical gaps in knowledge. The overall objectives of this application are to determine the therapeutic potential of CBD for SAH injury and elucidate mechanisms by which CBD improves vascular health. The central hypothesis is that daily CBD treatment, following experimental SAH, will improve vascular function to increase cerebral blood flow and prevent delayed cerebral ischemia, thereby improving functional outcomes. The rationale for this project is that determination of CBD’s therapeutic efficacy and associated mechanisms in the brain will generate a strong scientific framework from which new strategies for SAH therapy in patients can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Identify the optimal CBD dose to improve functional outcome following experimental SAH; and 2) Identify the impact of CBD therapy on cerebral microvessel pathology following experimental SAH. Under the first aim, multiple doses of CBD will be tested in mice following SAH injury (endovascular perforation) to determine the most effective dose that improves sensory/motor function and cognitive outcomes. For the second aim, the efficacy of CBD to reduce the development of vasospasm and blood-brain barrier permeability will be tested utilizing intravital microscopy and ex vivo micro-Computed Tomography imaging. The research proposed in this application is innovative because it proposes the use of a relatively safe compound with a wide variety of molecular targets capable of ameliorating multiple aspects of SAH pathology. The proposed research is significant because it is expected to provide scientific justification for the continued mechanistic investigation of CBD as a much- needed novel therapeutic for SAH patients, advancing the field of stroke research.