Role of Cannabidiol and Tetrahydrocannabivarin on Paclitaxel-Induced Neuropathic Pain in Rodents

The purpose of this study was to investigate the neuroprotective effects of phytocannabinoids, synthetic cannabidiol (CBD) and tetrahydrocannabivarin (THCV) and their combination on taxol induced peripheral neuropathy (PIPN) in mice. Briefly, six groups of C57BL/6J mice (n = 6) were used. PTX (8 mg/kg/day, i.p.) was given to the mice on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for their behavioral parameters and also at the end of the study, DRG collected from the animals were subjected to RNA sequence and westernblot analysis. Further, immunocytochemistry and mitochondrial functional assays were performed on cultured DRGs derived from SD rats. The combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by two folds as compared to individual treatments. KEGG (RNA Sequencing) identified P38-MAPK, AMPK, and PI3K-AKT pathways as potential CBD and THCV therapeutic targets. In PTX-treated animals, the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase was significantly reduced (p<0.001), whereas the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-, NLRP3 inflammasome, and caspase 3 was significantly increased (p<0.001) when compared to control group. In reversing these protein expressions, combination therapy outperformed single therapies. CBD and THCV treatment increased AMPK, Catalase, and Complex I expression while decreasing mitochondrial superoxides in DRG primary cultures. In mice and DRG primary cultures, WAY100135 and rimonabant inhibited the effects of CBD and THCV by blocking 5 HT1A and CB1 receptors. In conclusion, entourage effect of CBD and THCV combination against PIPN appears to protect neurons in mice by modulating 5HT1A and CB1 receptors, respectively.

Plasma Total Tau and Neurobehavioral Symptoms of Cognitive Decline in Cognitively Normal Older Adults

Depression and related neurobehavioral symptoms are common features of Alzheimer’s disease and other dementias. The presence of these potentially modifiable neurobehavioral symptoms in cognitively intact older adults may represent an early indication of pathophysiological processes in the brain. Tau pathology is a key feature of a number of dementias. A number of studies have found an association between tau and neurobehavioral symptoms. The current study investigated the relationship of a blood-based biomarker of tau and symptoms of depression, anxiety, worry, and sleep disturbances in 538 community based, cognitively normal older adults. Logistic regression revealed no significant relationship between plasma total tau and any measures of neurobehavioral symptoms. To assess the impact of level of tau on these relationships, participants were divided into those in the highest quintile of tau and those in the lower four quintiles. Regression analyses showed a significant relationship between level of plasma total tau and measures of depression, apathy, anxiety, worry and sleep. The presence of higher levels of plasma tau and elevated neurobehavioral symptoms may be an early indicator of cognitive decline and prodromal Alzheimer’s disease. Longitudinal research is needed to evaluate the impact of these factors on the development of dementia and may suggest areas for early intervention.

Neurotoxic Agents and Peripheral Neuropathy

Neurotoxicity may develop with exposure to various substances such as antibiotics, chemotherapeutics, heavy metals, and solvents. Some plants and fungi are also known to be neurotoxic. Neurotoxicity can develop acutely within hours, or it can develop as a result of exposure for years. Neurotoxicity can be presented with central or peripheral nervous system findings such as neurobehavioral symptoms, extrapyramidal signs, peripheral neuropathy. Peripheral nerve fibers are affected in different ways by neurotoxicant injury. The pattern of injury depends on the target structure involved. The focus of this chapter includes signs, symptoms, pathophysiology, and treatment options of neurotoxicity.

Neurobehavioral Symptoms in U.S. Special Operations Forces in Rehabilitation After Traumatic Brain Injury: A TBI Model Systems Study

ABSTRACT Introduction Special Operations Forces (SOF) personnel are at increased risk for traumatic brain injury (TBI), when compared with conventional forces (CF). Prior studies of TBI in military samples have not typically investigated SOF vs. CF as specific subgroups, despite documented differences in premorbid resilience and post-injury comorbidity burden. The aim of the current study was to compare SOF vs. CF on the presence of neurobehavioral symptoms after TBI, as well as factors influencing perception of symptom intensity. Materials and Methods This study conducted an analysis of the prospective veterans affairs (VA) TBI Model Systems Cohort, which includes service members and veterans (SM/V) who received inpatient rehabilitation for TBI at one of the five VA Polytrauma Rehabilitation Centers. Of those with known SOF status (N = 342), 129 participants identified as SOF (average age = 43 years, 98% male) and 213 identified as CF (average age = 38.7 years, 91% male). SOF vs. CF were compared on demographics, injury characteristics, and psychological and behavioral health symptoms. These variables were then used to predict neurobehavioral symptom severity in univariable and multivariable analyses. Results SOF personnel reported significantly greater posttraumatic stress disorder (PTSD) symptoms but less alcohol and drug use than the CF. SOF also reported greater neurobehavioral symptoms. When examining those with TBIs of all severities, SOF status was not associated with neurobehavioral symptom severity, while race, mechanism of TBI, and PTSD symptoms were. When examining only those with mTBI, SOF status was associated with lower neurobehavioral symptoms, while PTSD severity, white race, and certain mechanisms of injury were associated with greater neurobehavioral symptoms. Conclusions Among those receiving inpatient treatment for TBI, SOF SM/V reported higher neurobehavioral and symptom severity. PTSD was the strongest predictor of neurobehavioral symptoms and should be considered an important treatment target in both SOF and CF with co-morbid PTSD/TBI. A proactive human performance approach towards identification and treatment of psychological and neurobehavioral symptoms is recommended for SOF.

Neuronally-derived tau is increased in experienced breachers and is associated with neurobehavioral symptoms

Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aβ42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (−0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aβ42 or in serum levels of NF-L, tau, or Aβ42 (p’s > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score (F(1,14) = 7.702, p = 0.015, R2 = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.