Abstracts

Rationale: Traumatic brain injury (TBI) quickly leads to profound local hypoperfusion, ischemia, metabolic dysregulation and disturbances in glutamate homeostatic mechanisms, oxidative stress, free radical production, and lipid peroxidation triggering common cell death pathways that lead to neuropathology, behavioral deficits and increased risk of post-traumatic epilepsy (PTE) and post-traumatic stress disorder (PTSD). Cannabidiol (CBD), the major non-psychotropic cannabinoid, has anti-convulsant, anti-inflammatory, anti-nociceptive, anti-oxidant, and immuno-suppressive properties which may abate TBI-induced pathophysiology. However, systemic administration of CBD alone after TBI would be restricted due to the acute hypoperfusion at the site of impact limiting access to the contused tissue. Therefore, we hypothesized that dual therapeutic administration of CBD directly to the brain contusion site together with systemic supplementation will optimize drug delivery to the injured tissue to effectively reduce local neural excitation, inflammation, and glutamate pathogenicity to restore neurological outcomes following TBI.

Methods: Adult rats were cortically contused unilaterally over the motor cortex under anesthesia in a stereotactic apparatus connected with a weight-drop apparatus. CBD was delivered over the dura at the contusion site (CBDi) in an infused gelfoam matrix as well as systemically by injection (CBD.IP). Animals were also treated only with the CBD-infused implant or IP injection for comparison. Vestibulomotor function and anxiety were simultaneously determined with the beam balance test and collecting defecation scores on Days 1-28 following TBI. Learning and memory tests included the spontaneous alternating T-maze and object recognition. Brains were paraffin sectioned and processed and analyzed with Nissl, NeuN and GFAP staining methods.

Results: Post-injury administration of CBDi+IP greatly reduced defecation scores, lesion volume, the loss of neurons in the ipsilateral hippocampus, the number of injured neurons of the contralateral hippocampus, and reversed TBI-induced glial fibrillary acidic protein (GFAP) upregulation which was superior to either CBD.IP or CBDi treatment alone. Vestibulomotor performance was restored by 12 days post-TBI and sustained through 28 days. CBD treated rats exhibited preinjury levels of spontaneous alternation on the T-maze and exploration of novel objects consistent with restored cognitive function.

Conclusions: The results suggest that dual therapy by targeting the site of injury internally with an infused CBD carrier that is supplemented systemically can offer a more effective countermeasure than systemic or implant treatment alone for opposing the deleterious effects of penetrating head wounds. Whether the beneficial effect of the CBDi+IP treatment was due to anti-inflammatory, anti-convulsant and anti-oxidative stress properties or other undefined mechanisms is yet to be elucidated.

Funding: Please list any funding that was received in support of this abstract.: Private donations.