Traumatic Brain Injury Leads to Development of Parkinson's Disease Related Pathology in Mice

Abstract

Traumatic brain injury (TBI) is a major health and socio-economic problem that affects all societies. This condition results from the application of external physical strength to the brain that leads to transitory or permanent structural and functional impairments. Moreover, TBI is a risk factor for neurodegeneration and can e.g., increase the risk for Parkinson's disease (PD), a late-onset neurodegenerative disorder with loss of dopaminergic neurons in substantia nigra. In this study, we wanted to explore the possible development of PD-related pathology within the context of an experimental model of TBI. Traumatic brain injury was induced in mice by controlled cortical impact. At different time points behavioral tests (open field, elevated plus maze tests, and Barnes maze) were performed: The animals were sacrificed 30 days after the impact and the brains were processed for Western blot and immunohistochemical analyses. Following TBI there was a significant decrease in expression of tyrosine hydroxylase and dopamine transporter in the substantia nigra as well as significant behavioral alterations. In addition, a strong increase in neuroinflammation was evident, as shown by increased levels of cyclooxygenase-2 and inducible nitric oxide synthase as well as IκB-α degradation and nuclear-κB translocation. Moreover, neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, nerve growth factor, and glial cell line-derived neurotrophic factor were decreased 30 days post-TBI. Interestingly, we observed a significant accumulation of α-synuclein in microglia compared to astrocytes. This study suggests that PD-related molecular events can be triggered upon TBI. The biological mechanisms linking brain trauma and neurodegenerative diseases need to be further investigated.

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

“…Remarkably, full amelioration of the toxic effects of glutamate and hydrogen peroxide were achieved at 1 and 10 nM, respectively, in SH-hGLP-1R#9 cells. In light of the reported dopaminergic neuronal cell loss following mild to moderate TBI in rodent models (Hutson et al, 2011; Bales et al, 2010; Acosta et al, 2015; Impellizzeri et al, 2016), up regulation of PD associated pathways instigated by mTBI in rodents (Tweedie et al, 2013b), elevated risk of PD following TBI in humans (Gardner et al, 2015; Crane et al, 2016), and progression of PD in humans by TBI (Schiehser et al, 2016; Crane et al, 2016), we evaluated the ability of Twincretin to protect cultured dopaminergic primary VM neurons from cellular demise. Twincretin (10 to 1000 nM) significantly increased TH immunoreactivity in these neurons exposed to toxic doses of 6OHDA, as compared to neurons exposed to the toxic insult alone.…”

“…Using human neuroblastoma cells, we show that twincretin has activity at both the GLP-1R and GIPR, and that it significantly reduces cell death in response to toxic doses of glutamate and hydrogen peroxide, mimicking in part the neuroinflammatory conditions present in the secondary phase of mTBI (Morganti-Kossmann et al, 2002; Barkhoudarian et al, 2011; Baratz et al, 2011; Walker and Tesco, 2013; Greig et al, 2014; Barkhoudarian et al, 2016). In light of the vulnerability of dopaminergic neurons to TBI (Shahaduzzaman et al, 2013; Acosta et al, 2015; Impellizzeri et al, 2016), this neuroprotective effect is recapitulated in a dopaminergic neuronal cell group; specifically, primary cultures of rat ventral mesencephalon (VM) neurons. Twincretin is also shown to improve upon the effects of the single-receptor agonists, Ex-4 and GIP.…”

Loss of highwire protects against the deleterious effects of traumatic brain injury in Drosophila Melanogaster

“…3B). [40,44,45] The number of neurons in the PPL1 cluster is remarkably consistent in wild-type ies, with an average of 12 neurons. Immunostaining for tyrosine hydroxylase (TH) demonstrated a signi cant decrease in the number of neurons in the PPL1 cluster following injury in hiw WT ies.…”

Inhibition of mammalian target of rapamycin (mTOR) improves neurobehavioral deficit and modulates inflammatory response after traumatic brain injury

“…For graphic representation of densitometric analyses, we measured the intensity of positive staining (brown staining) by computer-assisted color image analysis (Leica QWin V3, UK). The percentage area of immunoreactivity (determined by the number of positive pixels) was expressed as percent of total tissue area (red staining) as seen previously (17).…”