Neuroprotective, anticonvulsant, and proconvulsant effects of cannabinoids following neurotrauma

Title : Neuroprotective, anticonvulsant, and proconvulsant effects of cannabinoids following neurotrauma

Abstract:

Traumatic brain (TBI) injuries result in profound local hypoperfusion, ischemia, chronic inflammation and refractory seizures (post-traumatic epilepsy (PTE) and restrict drug delivery to the site of impact so that peripheral treatment alone would have limited access to the site of injury during the most critical phases of neurotrauma. Cannabidiol (CBD), the major non-psychotropic cannabinoid, has anti-convulsant, anti-inflammatory, anti-nociceptive, antioxidant, and immuno-suppressive properties not fully understood. In pre-juvenile rats, microinjection of CBD attenuated kainate (KA)-induced seizures to a greater extent than intraperitoneal injection, indicating that local drug administration was more effective. In adult rats after experimental TBI, our modified CBD-infused implant applied extradural with oil injection supplementation restored vestibulomotor and cognitive functions compared to systemic treatment alone. We questioned whether the CBD or the low concentrations of THC in the extract was responsible for behavioral and cellular recovery. We hypothesized that an optimal ratio of cannabidiol (CBD) to tetrahydrocannabinol (THC) is required to protect against neuropathological consequences following TBI greater than either substance alone. Varied CBD:THC extract concentrations were compared with hemp CBD lacking THC (CBD₀). Neurons, glia, and parvalbumin interneurons (PV-INs) were evaluated. Weight loss was observed following high doses of THC dominant cannabis, THC_100:1. Neuroscores and vestibulomotor performance were restored optimally with CBD:THC_300:1-10:1. However, THC dominant treatments resulted in early onset to spontaneous seizures post-TBI. In a non-reward T-maze, the CBD_10:1 group had the highest alternation rates; TBI + vehicle, CBD₀, CBD_1:1, and THC_100:1 treatment groups had the lowest. The novel object recognition memory task showed CBD_300:1 treated animals had the best performance, while TBI or THC_100:1 treated groups had the worst. The forced swim test (FST) showed immobility time was highest after TBI and lowest after THC_100:1 treatment. The elevated plus maze (EPM) revealed the CBD₀ group spent the most time in closed arms. Both tests indicate that reduced anxiety was THC dependent. All combinations resulted in reduced injury but CBD_10:1 and THC_20:1 gave the most protection and THC_100:1 the least. Reduced anxiety level was THC dependent but higher doses were pro-convulsant cautioning THC dosing. Reduced GFAP labeling was highest with CBD dominant cannabis supporting its neuroprotective role against inflammation. Rescue of diminished bilateral PV-INs was observed within the hippocampus and medial prefrontal cortex (mPFC) with CBD dominant treatment (CBD₃₀₀, CBD₀) supporting their anticonvulsant effect.  Loss of PV-INs with THC dominant treatment supports their proconvulsant effect. Thus, CBD and THC have different beneficial therapeutic effects indicating an optimal concentration ratio is critical for optimal neuropathological therapeutics.

Keywords: Cannabinoids, Neurotrauma, Neuroprotection, Post-Traumatic Epilepsy

Annotation: Traumatic brain (TBI) injuries result in profound local hypoperfusion, ischemia, chronic inflammation, and metabolic dysregulation which restrict drug delivery to the site of impact so that peripheral treatment alone would have limited access to the site of injury during the most critical phases of neurotrauma. Cannabidiol (CBD), the major non-psychotropic cannabinoid, has anti-convulsant, anti-inflammatory, anti-nociceptive, antioxidant, and immuno-suppressive properties that may treat both primary and secondary injury associated with TBI. Recently we found that direct delivery to the wound site and the ratio of CBD to tetrahydrocannabidol (THC) (CBD:THC) may be critical for motor and cognitive recovery. Determining the optimal ratio of CBD:THC will allow clinicians to treat patients with optimal cannabinoid combinations to combat excitotoxic cascades that quickly follow TBI and prevent the onset to PTE.

Biography:

Dr. Linda K Friedman, Associate Professor of Neuroscience, New York Medical College, grew up in Massachusetts and received her Bachelor's degree from the University of Louisville in 1980. She obtained her MA and PhD degrees from the City University of New York, Mount Sinai in 1988. She was a postdoc at Downstate Medical Center, Brooklyn and at Albert Einstein College of Medicine in 1988-1994 and was appointed Instructor Professor in 1994-1996. She was appointed to Assistant and Associate Professor at NJ Neuroscience Institute Seton Hall University 1997-2012, then transferred to New York Medical College in 2012 to present. She has focused on pre-clinical models to study neurotoxicity, delayed neurodegeneration, novel drug therapy, that may lead to neuroprotective and cognitive benefits. She has many awards and honors: 1992, 1997, Annual American Epilepsy Society, Seattle, Junior Investigator Awardee; Red Ribbon Best Poster Award in Basic Research at the 114th Annual Osteopathic Association Convention. 2012, Platform Presentation Selection: Annual American Epilepsy Society Convention. Chosen in Top 10%; 2021: Platform Presentation Selection: “Chronic postnatal subconvulsive activity alters mood, cognition, seizure severity, NeuN antigenicity and polyphosphoinositide hydrolysis within limbic structures of juvenile rats”. Friedman LK, Tenth and 11^th International Meetings on Metabotropic Glutamate Receptors. AMPA and mGluR expression after chronic anticonvulsant treatment and epilepsy. Taormina Sicily-Italy.