Brain trauma induces inflammation in both the endothelium and the brain parenchyma, collectively termed the neurovascular unit. While neurons die quickly by necrosis following traumatic brain injury (TBI), a vicious cycle of inflammation in endothelial cells exacerbates the injury. In activated endothelial cells, excessive superoxide reacts with nitric oxide (NO) to form peroxynitrite. At high levels following TBI, peroxynitrite is involved in blood brain barrier (BBB) leakage, altered enzymatic functions, and neurobehavior impairment. It activates AMP Kinase (AMPK), which in turn may up regulate the superoxide-producing activity of endothelial nitric oxide synthase (eNOS), and thus maintains a vicious cycle of neuroinflammatory secondary injury. The nitrosylating agent S-nitrosoglutathione (GSNO) is capable of reducing the levels of peroxynitrite and inhibiting the activity of AMPK. It also restores the levels of glutathione and protects the integrity of the neurovascular unit. Therefore, this study will investigate whether GSNO treatment ameliorates TBI-induced neuroinflammatory damage to the neurovascular unit via nitrosylation. We hypothesize that GSNO blocks the vicious AMPK/eNOS/peroxynitrite cycle, thus reducing the neurovascular injury and aiding functional recovery in TBI.
In Specific Aim 1, pharmacological agents (GSNO, a peroxynitrite scavenger, and an AMPK selective inhibitor) will be used as therapeutic tools to dissect the regulation of AMPK and amelioration of TBI in a controlled cortical impact mouse model.
In Specific Aim 2, the elucidated mechanisms will be further examined and validated using AMPK alpha 1/2 knockout mice, AMPK alpha over-expressing transgenic mice, and wild type mice.
In Specific Aim 3, we will determine whether GSNO-mediated nitrosylation of either AMPK or its upstream kinase LKB1 is responsible for the inhibition of aberrant eNOS activity and the reduced formation of peroxynitrite. The complementary pharmacological and genetic approach will determine the role of AMPK in TBI. GSNO, unlike conventional NO donors, is a non-toxic endogenous NO modulator and nitrosylating agent. Understanding S-nitrosylation mechanism and the unique AMPK/eNOS/peroxynitrite pathway may lead to new strategies for the treatment of neuroinflammatory brain trauma that target not only its neuronal consequences but also its vascular causes and exacerbations.
As a consequence of war, accidents and sport injury, an increasing number of young Americans are suffering from brain trauma. Current treatment is limited to supportive care because the neuroinflammatory mechanisms of traumatic brain injury are not well understood. The success of this proposed mechanistic intervention using S-nitrosoglutathione would provide a novel neurovascular approach to treating brain trauma.
|Samuvel, Devadoss J; Shunmugavel, Anandakumar; Singh, Avtar K et al. (2016) S-Nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis. J Pharm Pharmacol 68:1310-9|
|Khan, Mushfiquddin; Dhammu, Tajinder S; Baarine, Mauhamad et al. (2016) GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1Î±. Behav Brain Res :|
|Khan, Mushfiquddin; Dhammu, Tajinder S; Matsuda, Fumiyo et al. (2016) Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI. Brain Res 1630:159-70|
|Khan, Mushfiquddin; Shunmugavel, Anandakumar; Dhammu, Tajinder S et al. (2015) Oral administration of cytosolic PLA2 inhibitor arachidonyl trifluoromethyl ketone ameliorates cauda equina compression injury in rats. J Neuroinflammation 12:94|
|Paintlia, Manjeet K; Singh, Inderjit; Singh, Avtar K (2015) Effect of vitamin D3 intake on the onset of disease in a murine model of human Krabbe disease. J Neurosci Res 93:28-42|
|Won, Je-Seong; Annamalai, Balasubramaniam; Choi, Seungho et al. (2015) S-nitrosoglutathione reduces tau hyper-phosphorylation and provides neuroprotection in rat model of chronic cerebral hypoperfusion. Brain Res 1624:359-69|
|Samuvel, Devadoss J; Saxena, Nishant; Dhindsa, Jasdeep S et al. (2015) AKP-11 - A Novel S1P1 Agonist with Favorable Safety Profile Attenuates Experimental Autoimmune Encephalomyelitis in Rat Model of Multiple Sclerosis. PLoS One 10:e0141781|
|Baarine, Mauhamad; Khan, Mushfiquddin; Singh, Avtar et al. (2015) Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy. PLoS One 10:e0143238|
|Annamalai, Balasubramaniam; Won, Je-Seong; Choi, Seungho et al. (2015) Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation. Biochem Biophys Res Commun 458:214-9|
|Kaliyaperumal, Kolanjiappan; Sharma, Anand K; McDonald, Daniel G et al. (2015) S-Nitrosoglutathione-mediated STAT3 regulation in efficacy of radiotherapy and cisplatin therapy in head and neck squamous cell carcinoma. Redox Biol 6:41-50|
Showing the most recent 10 out of 23 publications