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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS086929-01A1
Application #
8816362
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912