Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes.

Mild traumatic brain injuries may result in cumulative brain damage and neurodegenerative disease. To date, there is no pharmaceutical intervention known to prevent these consequences. Hyperphosphorylated tau has been associated in this process, and protein phosphatase 2A 55 kDa regulatory B subunit (PP2A/PR55) - the major tau phosphatase - is decreased after a brain insult. Sodium selenate up-regulates PP2A/PR55 and dephosphorylates tau, and may hold promise as a treatment in the mild brain injury setting. Here we investigated sodium selenate treatment in rats given repeated mild traumatic brain injuries. Rats were given three mild fluid percussion injuries or three sham-injuries, and treated with sodium selenate (1 mg/kg/day) or saline-vehicle for three months before undergoing behavioral testing, MRI, and post-mortem analysis of brain tissue. Repeated mild traumatic brain injuries increased the phosphorylation of tau and decreased PP2A/PR55, whilst inducing brain atrophy and cognitive and sensorimotor deficits. Sodium selenate treatment increased PP2A/PR55, and decreased tau phosphorylation, brain damage, and cognitive and motor impairments in rats given repeated mild traumatic brain injuries. Our findings implicate PP2A/PR55 and tau as important mechanisms in the pathophysiological aftermath of repeated mild brain traumas, and support sodium selenate as a novel and translatable treatment for these common injuries.

Granulocyte-macrophage colony-stimulating factor is neuroprotective in experimental traumatic brain injury.

Traumatic brain injury (TBI) is an international health concern with a complex pathogenesis resulting in major long-term neurological, neurocognitive, and neuropsychiatric outcomes. Although neuroinflammation has been identified as an important pathophysiological process resulting from TBI, the function of specific inflammatory mediators in the aftermath of TBI remains poorly understood. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an inflammatory cytokine that has been reported to have neuroprotective effects in various animal models of neurodegenerative disease that share pathological similarities with TBI. The importance of GM-CSF in TBI has yet to be studied, however. We examined the role of GM-CSF in TBI by comparing the effects of a lateral fluid percussion (LFP) injury or sham injury in GM-CSF gene deficient (GM-CSF(-/-)) versus wild-type (WT) mice. After a 3-month recovery interval, mice were assessed using neuroimaging and behavioral outcomes. All mice given a LFP injury displayed significant brain atrophy and behavioral impairments compared with those given sham-injuries; however, this was significantly worse in the GM-CSF(-/-) mice compared with the WT mice. GM-CSF(-/-) mice given LFP injury also had reduced astrogliosis compared with their WT counterparts. These novel findings indicate that the inflammatory mediator, GM-CSF, may have significant protective properties in the chronic sequelae of experimental TBI and suggest that further research investigating GM-CSF and its potential benefits in the injured brain is warranted.