A novel method to promote behavioral improvement and enhance mitochondrial function following an embolic stroke

Abstract

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for stroke; tPA increases cerebral reperfusion, blood flow and improved behavior. Novel transcranial laser therapy (TLT) also enhances cerebral blood flow and activates mitochondrial function. Using the rabbit small clot embolic stroke model (RSCEM), we studied the effects of continuous wave TLT (7.5mW/cm2) alone or in combination with standardized intravenous (IV) tPA (3.3mg/kg) applied 1h post-embolization on 3 endpoints: 1) behavioral function measured 2 days [effective stroke dose (P50 in mg) producing neurological deficits in 50% of embolized rabbits], 2) intracerebral hemorrhage (ICH) rate, and 3) cortical adenosine-5′-triphosphate (ATP) content was measured 6h following embolization. TLT and tPA significantly (p<0.05) increased P50 values by 95% and 56% (p<0.05), respectively over control. TLT-tPA increased P50 by 136% over control (p<0.05). Embolization reduced cortical ATP content by 39%; decreases that were attenuated by either TLT or tPA treatment (p<0.05). TLT-tPA further enhanced cortical ATP levels 22% above that measured in naïve control. TLT and tPA both effectively and safely, without affecting ICH rate, improved behavioral outcome in embolized rabbits; and there was a trend (p>0.05) for the TLT-tPA combination to further increase P50. TLT and tPA both attenuated stroke-induced ATP deficits, and the combination of tPA and TLT produced an additive effect on ATP levels. This study demonstrates that the combination of TLT-tPA enhances ATP production, and suggests that tPA-induced reperfusion in combination with TLT neuroprotection therapy may optimally protect viable cells in the cortex measured using ATP levels as a marker.