Traumatic brain injury (TBI) is common and frequently associated with potential long-term disability and mortality. TBI is primarily a consequence of a direct or indirect biomechanical force on brain tissues and followed by secondary injury cascade, ranging from changes in cerebral blood flow, increased intracranial pressure. Blood-brain barrier (BBB) dysfunction, edema formation, inflammation, excitotoxicity and cell death. To date, treatment strategies targeting neuronal rescue after TBI have not been clinically successful;therefore, treatments targeting the expanded vascular neural network (VNN) need to be developed not only for TBI patients but also for those with subarachnoid (SAH) and intracerebral hemorrhage (ICH). Recent studies have demonstrated that Caveolins (Cav) play a central role in several vascular diseases or injuries, with a potential protective role by inhibition of endothelial nitric oxide synthase (eNOS) and activation of c-Jun N terminal kinase (c-JNK). Both of these pathways play a detrimental role after injury in the VNN. A synthetic peptide, Cav-AP, reproduces the endogenous Cav functions by binding and inhibiting eNOS and JNK, and is now in development for cancer treatment. The role of Cav-1 will be investigated in a TBI rat model, by: i) decreasing Cav-1 with siRNA;and ii) mimicking Cav-1 functions by injection of Cav- AP after injury. We will also investigate the molecular mechanisms by testing: i) the level of activation of eNOS and JNK after TBI and Cav-AP treatment within the VNN, ii) with injection of an eNOS inhibitor (LNIO) and iii) treatment by a peptide D-JNKI inhibitor of the JNK pathway. Finally, Cav-AP will be tested as a potential treatment in SAH and ICH. Understanding the roles of Cav-1, eNOS and the JNK pathway in brain vascular system will provide avenues for development of therapeutic targets towards the VNN in hemorrhagic diseases.

Public Health Relevance

Traumatic brain injury (TBI) is frequently associated with cerebral vascular dysfunctions with a high risk of long-term disability and mortality. A protein involved in the formation ofthe caveolae, caveolin-1 (Cav-1), is involved in the pathophysiology of cerebral vessels after brain injuries. A novel agent Cav-AP, which mimics a subdomain of Cav-1, will be tested to inhibit the activation of c-Jun N terminal kinase (JNK) and endothelial nitric oxide .synthase (eNOS) and will have a synergistic effect in reducing vascular dysfunctions after TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Loma Linda University
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Zhan, Yan; Krafft, Paul R; Lekic, Tim et al. (2015) Imatinib preserves blood-brain barrier integrity following experimental subarachnoid hemorrhage in rats. J Neurosci Res 93:94-103
Zheng, Yun; Hu, Qin; Manaenko, Anatol et al. (2015) 17?-Estradiol attenuates hematoma expansion through estrogen receptor ?/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice. Stroke 46:485-91
Liu, Fei; Hu, Qin; Li, Bo et al. (2014) Recombinant milk fat globule-EGF factor-8 reduces oxidative stress via integrin ?3/nuclear factor erythroid 2-related factor 2/heme oxygenase pathway in subarachnoid hemorrhage rats. Stroke 45:3691-7
Chen, Sheng; Feng, Hua; Sherchan, Prativa et al. (2014) Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol 115:64-91
Fujii, Mutsumi; Sherchan, Prativa; Soejima, Yoshiteru et al. (2014) Cannabinoid receptor type 2 agonist attenuates apoptosis by activation of phosphorylated CREB-Bcl-2 pathway after subarachnoid hemorrhage in rats. Exp Neurol 261:396-403
Krafft, Paul R; McBride, Devin W; Lekic, Tim et al. (2014) Correlation between subacute sensorimotor deficits and brain edema in two mouse models of intracerebral hemorrhage. Behav Brain Res 264:151-60
Ma, Qingyi; Chen, Sheng; Hu, Qin et al. (2014) Reply: To PMID 24273204. Ann Neurol 75:972-3
Li, Qian; Khatibi, Nikan; Zhang, John H (2014) Vascular neural network: the importance of vein drainage in stroke. Transl Stroke Res 5:163-6
Altay, Orhan; Suzuki, Hidenori; Hasegawa, Yu et al. (2014) Isoflurane on brain inflammation. Neurobiol Dis 62:365-71
Fujii, Mutsumi; Sherchan, Prativa; Krafft, Paul R et al. (2014) Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats. J Neurol Sci 342:101-6

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