Transient global cerebral ischemia (GCI) during cardiac arrest affects 300,000 Americans each year, and in many cases, results in delayed death of hippocampal CA1 neurons and severe cognitive deficits. Current therapies are ineffective and only offer a short therapeutic window. Low-level Laser/Light Therapy (LLLT) is widely practiced by directly applying a low energy laser or light emitting diodes (LED) to a specific area of interest on the body. As a noninvasive procedure, the laser/light can penetrate the animal skull and brain to a depth of 2.5-3 cm. Our preliminary work in the GCI animal model has shown that LLLT 3 h after GCI strongly protects the CA1 pyramidal regions. This exciting observation has led to hope that further studies on the mechanisms underlying LLLT neuroprotection following GCI could potentially lead to new therapies in humans, which would allow rescue of hippocampal CA1 neurons in the human brain following cardiac arrest with an extended therapeutic window. The overall goal of the current proposal is to delineate the optimal wavelengths, doses, and time window of LLLT benefits, and to elucidate how LLLT protects the brain following GCI. We hypothesize that cerebral ischemic reperfusion induces ROS production and ATP overloading from dysfunctional mitochondria in neurons. This leads to subsequent enhanced oxidative damage and NLRP3 inflammasome cascade signaling, resulting in delayed CA1 neuronal death and cognitive deficits. LLLT is able to preserve mitochondrial integrity and membrane potential, blocking ROS production and ATP overloading. We propose that LLLT stimulates mitochondria-derived nitric oxide (NO) release to inhibit the activation of NLRP3 inflammasome (via S-nitrosylation of NLRP3) and to activate Nrf2 (via S-nitrosylation of Keap1 and Nrf2 release). We further hypothesize that LLLT can exert its beneficial actions by boosting Nrf2-regulated gene expression (e.g. Trx and SOD2) to counteract the NLRP3 inflammasome cascade and the oxidative damage induced by dysfunctional mitochondria after GCI. The proposed preclinical studies would advance the field by being the first to determine the potential efficacy of LLLT for protection of the brain following GCI.
Specific Aim 1 would test the hypothesis that LLLT exerts neuroprotection and improves functional outcome after GCI.
Specific Aim 2 would test the hypothesis that LLLT reduces ischemic oxidative damage and functional deficits via the activation of the Nrf2 pathway following GCI.
Specific Aim 3 would test the hypothesis that LLLT prevents NLRP3 inflammasome activation by preserving mitochondrial integrity and promoting Nrf2-regulated gene expression.
Cardiac arrests and the consequent global cerebral ischemia is one of the leading causes of death and permanent disability in the United States, and new neuroprotective therapies are urgently needed. This proposal meets this critical need as it will examine the efficacy and potential mechanisms of a Low-level Laser/Light Therapy (LLLT) for protection of the brain following cardiac arrest.
|Tucker, Donovan; Lu, Yujiao; Zhang, Quanguang (2018) From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Mol Neurobiol 55:5137-5153|
|Tucker, Lorelei Donovan; Lu, Yujiao; Dong, Yan et al. (2018) Photobiomodulation Therapy Attenuates Hypoxic-Ischemic Injury in a Neonatal Rat Model. J Mol Neurosci 65:514-526|
|Wu, Chongyun; Yang, Luodan; Tucker, Donovan et al. (2018) Beneficial Effects of Exercise Pretreatment in a Sporadic Alzheimer's Rat Model. Med Sci Sports Exerc 50:945-956|
|Wang, Ruimin; Dong, Yan; Lu, Yujiao et al. (2018) Photobiomodulation for Global Cerebral Ischemia: Targeting Mitochondrial Dynamics and Functions. Mol Neurobiol :|
|Li, Lei; Yang, Rongli; Li, Pingjing et al. (2018) Combination Treatment with Methylene Blue and Hypothermia in Global Cerebral Ischemia. Mol Neurobiol 55:2042-2055|
|Zhang, Juan; Tucker, Lorelei Donovan; DongYan et al. (2018) Tert-butylhydroquinone post-treatment attenuates neonatal hypoxic-ischemic brain damage in rats. Neurochem Int 116:1-12|
|Yang, Luodan; Tucker, Donovan; Dong, Yan et al. (2018) Photobiomodulation therapy promotes neurogenesis by improving post-stroke local microenvironment and stimulating neuroprogenitor cells. Exp Neurol 299:86-96|
|Ahmed, Mohammad Ejaz; Dong, Yan; Lu, Yujiao et al. (2017) Beneficial Effects of a CaMKII? Inhibitor TatCN21 Peptide in Global Cerebral Ischemia. J Mol Neurosci 61:42-51|
|Zhao, Ningjun; Zhuo, Xiaoying; Lu, Yujiao et al. (2017) Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia. Mol Neurobiol 54:4936-4952|
|Lu, Yujiao; Wang, Ruimin; Dong, Yan et al. (2017) Low-level laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging 49:165-182|
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