The goal of this research is to minimize the secondary cell death and resultant morbidity following traumatic brain injury (TBI). Clinical interventions to improve outcome following TBI are extremely limited. Mitochondrial dysfunction is a pivotal link in the neuropathological sequalae of traumatic brain injury (TBI). TBI-induced increases in mitochondrial Ca2+ cycling/overload ultimately lead to opening of the mitochondrial permeability transition pore (mPTP). This pore, located on the inner mitochondrial membrane, opens in response to elevated Ca2+ and oxidative stress, and is gated by the mitochondrial protein cyclophilin D (CypD). When prolonged, mPTP opening is catastrophic as a result of the loss of mitochondrial membrane potential, and the release of calcium and death-related proteins from mitochondria. The goal of this research is to minimize the secondary cell death and resultant morbidity following TBI by limiting mPTP opening. The immunosuppressant Cyclosporin A (CsA) inhibits mPTP opening by binding to CypD. We and others previously demonstrated that CsA reduces the extent of tissue damage when administered following experimental TBI. Unfortunately, CsA is toxic at high concentrations, resulting from its inhibition of calcineurin. Recently we have demonstrated that CypD levels in primary neurons are approximately double the levels found in astrocytes and that CypD levels are also significantly higher in synaptic mitochondria (neuronal origin) compared to non-synaptic mitochondria (predominately non-neuronal origin). As a result of their high CypD content, we hypothesize that neuronal mitochondria are more vulnerable to mPTP opening and also require greater CsA levels to inhibit mPTP opening. To test this hypothesis we propose to use genetic and newer pharmacologic approaches to inhibit CypD following neuronal injury. Specifically, we will use CypD knockout mice and a CsA derivative, NIM811, which does not bind to or inhibit calcineurin.
The specific aims are: 1: To evaluate the hypothesis that the high CypD content of neuronal mitochondria enhances vulnerability to mPTP opening following insults that result in elevated intracellular Ca2+ and oxidative stress. 2: To evaluate the hypothesis that the levels of the CypD inhibitor NIM811 required to protect neurons from excitotoxic insult is proportional to their CypD content. 3: To examine the hypothesis that mitochondrial CypD levels modulate the neuropathologic and functional outcome following TBI in mice. 4: To examine the hypothesis that CypD inhibitor NIM811 reduces tissue damage and improves functional outcome following TBI. Based on the results of these studies, we anticipate that NIM811 will exhibit strong potential as novel therapy for TBI.

Public Health Relevance

Traumatic brain injury (TBI) is a devastating healthcare problem in the United States, with no pharmacological treatments currently approved for clinical intervention following injury. Improved TBI treatment options are urgently needed. This proposal examines the potential of NIM811, a derivative of CsA, to limit the brain damage and dysfunction resulting from TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (03))
Program Officer
Hicks, Ramona R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Lyons, Danielle N; Zhang, Liping; Pandya, Jignesh D et al. (2018) Combination Drug Therapy of Pioglitazone and D-cycloserine Attenuates Chronic Orofacial Neuropathic Pain and Anxiety by Improving Mitochondrial Function Following Trigeminal Nerve Injury. Clin J Pain 34:168-177
Kulbe, Jacqueline R; Geddes, James W (2016) Current status of fluid biomarkers in mild traumatic brain injury. Exp Neurol 275 Pt 3:334-352
Pandya, Jignesh D; Royland, Joyce E; MacPhail, Robert C et al. (2016) Age- and brain region-specific differences in mitochondrial bioenergetics in Brown Norway rats. Neurobiol Aging 42:25-34
Kim, Do Young; Simeone, Kristina A; Simeone, Timothy A et al. (2015) Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann Neurol 78:77-87
Pandya, Jignesh D; Readnower, Ryan D; Patel, Samir P et al. (2014) N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI. Exp Neurol 257:106-13
Visavadiya, Nishant P; McEwen, Melanie L; Pandya, Jignesh D et al. (2013) Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage. Toxicol In Vitro 27:788-97
Avery, Michelle A; Rooney, Timothy M; Pandya, Jignesh D et al. (2012) WldS prevents axon degeneration through increased mitochondrial flux and enhanced mitochondrial Ca2+ buffering. Curr Biol 22:596-600
Sauerbeck, Andrew; Hunter, Randy; Bing, Guoying et al. (2012) Traumatic brain injury and trichloroethylene exposure interact and produce functional, histological, and mitochondrial deficits. Exp Neurol 234:85-94
Sauerbeck, Andrew; Gao, Jianxin; Readnower, Ryan et al. (2011) Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp Neurol 227:128-35
Sauerbeck, Andrew; Pandya, Jignesh; Singh, Indrapal et al. (2011) Analysis of regional brain mitochondrial bioenergetics and susceptibility to mitochondrial inhibition utilizing a microplate based system. J Neurosci Methods 198:36-43

Showing the most recent 10 out of 13 publications