Riya Sreenivasan

 Introduction. Traumatic brain injury is a disruption in brain function after a head injury and can lead to the development of an acquired condition called post-traumatic epilepsy. This condition is characterized by unprovoked and recurrent seizures beginning at least 1 week after injury.  Traumatic brain injuries account for 4% of PTE cases. Prolonged and uncontrolled PTE has been correlated with increasing rates of depression, mortality, comorbidity, and reduced quality of life in patients. Comorbidities include diseases like Alzheimer’s, dementia, and anxiety disorders. Though seizure drugs on the market have been used to treat PTE, it has been found to be drug resistant in approximately ⅓ of patients, making there a huge need for alternative therapies². An innate neuroinflammation response to TBI in the brain is characterized in part by a cascade of proinflammatory signals, an influx of leukocytes, and a breakdown of the brain’s blood brain barrier (BBB). Neuroinflammation alters the functions and connectivity of neurons, leading to chronic local neuronal hyperexcitability and susceptibility to seizures – this is called secondary neurodegeneration³. The endocannabinoid 2-AG was found to have neuroprotective properties when administered soon after traumatic brain injuries¹. Methods. Adult male mice were exposed to close head injuries and then tested for blood brain barrier integrity through injection with Evans Blue dye, removal of brains, and fluorescence measurement using a fluorospectrophotometer. PCR was then used to assess the expression of cytokines and low molecular weight antioxidants were measured through cyclic voltammetry¹. Results. 2-AG leads to decreased blood brain barrier permeability and inhibits the expression of the following proinflammatory cytokines: TNF-a, IL-1B and IL-6. Furthermore, it increased levels of endogenous antioxidants. Low molecular weight antioxidants (LMWA) are released naturally by the brain and help neutralize ROS and protect the BBB and brain from oxidative stress. The addition of 2-AG treatment was found to augment the release of LMWA 4 hours after traumatic brain injury. 2-AG inhibits the proinflammatory cytokine IL-2 expression through inhibition of NF-κB in thymocytes, a transcription factor that regulates the immune response. 2-AG inhibits the in-vitro production of TNF-α in macrophages and suppresses lipopolysaccharide-stimulated release of proinflammatory IL-6 in the brain. When administered soon after traumatic brain injury, 2-AG was found to also inhibit the proinflammatory cytokine IL-1β and reduce the permeability of the BBB¹. Conclusions. 2-AG and other drugs that modulate endocannabinoid levels could be potential therapeutic interventions for patients after traumatic brain injury to prevent the development of post-traumatic epilepsy through the degradation of the blood brain barrier and the existence of a highly proinflammatory environment in their brains.

1. Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, Shohami E. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory Neurobiol Dis. 2006 May;22(2):257-64. doi: 10.1016/j.nbd.2005.11.004.
2. Sharma R, Leung WL, Zamani A, O’Brien TJ, Casillas Espinosa PM, Semple BD. Neuroinflammation in Post-Traumatic Epilepsy: Pathophysiology and Tractable Therapeutic Brain Sci. 2019 Nov 9;9(11):318. doi: 10.3390/brainsci9110318.
3. Sharma S, Tiarks G, Haight J, Bassuk Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy. Front Mol Neurosci. 2021 Feb 23;14:612073. doi: 10.3389/fnmol.2021.612073.