Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189

Abstract

Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of θ (4-10 Hz) and β (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) within mPFC. These abnormalities might be linked to the impaired memory, depression, and persevering fear seen after mTBI. Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the proinflammatory M1 state to the prohealing M2 state by SMM-189.

Progress in brain cannabinoid CB2 receptor research: From genes to behavior

“…Surprisingly, these effects were reversed with JWH133 treatment (a CB2R agonist) but exacerbated by AM630 treatment (a CB2R antagonist) (Sun et al, 2017). In animal models of traumatic brain injury (TBI), administration of a CB2R inverse agonist attenuated neuronal death in the cortex, striatum and amygdala (Bu et al, 2016), and reversed TBI-induced electrophysiological changes in hippocampal and prefrontal cortex oscillatory activity (Liu et al, 2017b). In a rat model of vascular dementia, the CB2R agonist BCP improved learning and memory on the Morris water maze, increased cerebral blood flow, and upregulated CB2R expression in the hippocampus (Lou et al, 2017).…”

Toward development of clinically translatable diagnostic and prognostic metrics of traumatic brain injury using animal models: A review and a look forward

“…To control for the variability in subject sample and characteristics, animal models of TBI are a promising avenue to study the mechanisms of concussive injury from injury causation to changes to neural function, intracranial injury mechanisms, and histopathological changes post mortem. Research employing animal models of TBI combined with EEG measures have primarily used rats under lateral fluid percussion injury ( Biswas et al, 2018 ), projectile concussive impact ( Leung et al, 2014 ; Mountney et al, 2017 ), high deceleration impact system ( Napoli et al, 2012 ), a weight drop model ( Ucar et al, 2006 ), and mice under blast loading ( Liu et al, 2017 ) and also using the weight drop model ( Sabir et al, 2015 ). While differences observed in the power frequency bands between injured and non-injured animals were demonstrated, the measurement of EEG in these studies involved opening up the cranial vault and implanting electrodes directly on the brain.…”

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

“…In vivo animal studies showed that CB2R receptor is the main pharmacological target of natural or synthetic cannabinoids in protection against cognitive and motor impairment after TBI [ 1 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 54 , 55 , 57 , 58 , 59 , 60 ]. The inhibition of CB1R by SR141716 failed to show any beneficial effect on cognitive and motor impairment after TBI [ 50 ].…”

“…The main mechanisms through which cannabinoids improve cognitive and motor impairment after TBI are associated with decreasing the pro-inflammatory markers [ 1 , 44 , 46 , 47 , 48 , 52 , 53 , 57 , 58 ], decreasing oedema formation [ 44 , 45 , 47 , 54 , 55 , 58 , 60 ], decreasing BBB permeability [ 44 , 45 , 46 , 54 , 55 , 57 ], preventing neuronal cell loss [ 44 , 49 , 51 , 55 ] and increasing the levels of adherens jonction proteins [ 45 , 46 , 54 ].…”