Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson's-like pathology burden.

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson's disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden.

Sidestream Smoke Affects Dendritic Complexity and Astrocytes After Model Mild Closed Head Traumatic Brain Injury.

Mild traumatic brain injuries can have long-term consequences that interfere with the life of the patient and impose a burden on our health care system. Oxidative stress has been identified as a contributing factor for the progression of neurodegeneration following TBI. A major source of oxidative stress for many veterans is cigarette smoking and second-hand smoke, which has been shown to have an effect on TBI recovery. To examine the potential influences of second-hand smoke during recovery from TBI, we utilized a mouse model of closed head injury, followed by repeated exposure to cigarette smoke and treatment with a neuroprotective antioxidant. We found that neither the mild injuries nor the smoke exposure produced axonal damage detectable with amino cupric silver staining. However, complexity in the dendritic arbors was significantly reduced after mild TBI plus smoke exposure. In the hippocampus, there were astrocytic responses, including Cyp2e1 upregulation, after the injury and tobacco smoke insult. This study provides useful context for the importance of lifestyle changes, such as reducing or eliminating cigarette smoking, during recovery from TBI.

Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells.

Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism. Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 µM, insect repellants DEET 78 µM, and antitoxins PB 19 µM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.