Randomized Clinical Stroke Trials in 2007

This article reviews the randomized control trials (RCT’s) that were published in 2007 of emerging pharmacotherapies in patients with acute (≤ 2 weeks), sub-acute (2 to 12 weeks) and chronic (≥ 12 weeks) stroke. A Medline search generated 22 RCT’s in stroke in the year 2007 in the English language. These trials were primarily efficacy studies. These included the role of statins (an anti-lipid agent) in reducing post-stroke morbidity and mortality, and decreasing the carotid atherosclerotic plaque in middle aged patients at increased risk of cardiovascular disease; glucose-potassium-insulin infusion in hyperglyceamic acute stroke patients; pioglitazone (an anti-diabetic medication) to reduce recurrence of stroke in Type 2 diabetic patients; administration of intra-arterial urokinase (a thrombolytic agent) and the role of laser therapy in clot dissolution given that at present there is only one FDA approved thrombolytic agent (r TPA); benefit of warfarin (an anticoagulant) in elderly patients with atrial fibrillation in the community; NXY (a free radical trapping agent) and minocycline both tested as neuroprotectants; and zoledronate (an intravenous bisphosphonate) to prevent loss of bone mineral density of the affected extremity, and finally the role of nicardipine (a Calcium channel blocker) in the prevention of vasospasm, and hydrocortisone to prevent hyponatraemia after sub-arachnoid hemorrhage. Finally the role of non-pharmacotherapy like stents for patient’s with internal carotid artery dissection with tandem internal carotid and middle cerebral artery occlusion and in vertebral artery stenosis

Clinically Approved Heterocyclics Act on a Mitochondrial Target and Reduce Stroke-induced Pathology

Substantial evidence indicates that mitochondria are a major checkpoint in several pathways leading to neuronal cell death, but discerning critical propagation stages from downstream consequences has been difficult. The mitochondrial permeability transition (mPT) may be critical in stroke-related injury. To address this hypothesis, identify potential therapeutics, and screen for new uses for established drugs with known toxicity, 1,040 FDA-approved drugs and other bioactive compounds were tested as potential mPT inhibitors. We report the identification of 28 structurally related drugs, including tricyclic antidepressants and antipsychotics, capable of delaying the mPT. Clinically achievable doses of one drug in this general structural class that inhibits mPT, promethazine, were protective in both in vitro and mouse models of stroke. Specifically, promethazine protected primary neuronal cultures subjected to oxygen-glucose deprivation and reduced infarct size and neurological impairment in mice subjected to middle cerebral artery occlusion/reperfusion. These results, in conjunction with new insights provided to older studies, (a) suggest a class of safe, tolerable drugs for stroke and neurodegeneration; (b) provide new tools for understanding mitochondrial roles in neuronal cell death; (c) demonstrate the clinical/experimental value of screening collections of bioactive compounds enriched in clinically available agents; and (d) provide discovery-based evidence that mPT is an essential, causative event in stroke-related injury

Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat

The African naked mole-rat’s ($\textit{Heterocephalus glaber}$) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.Work was supported aEuropean Research Council (294678), the Deutsche Forschungsgemeinschaft SFB 665 and Go865/9-1, NSF (grant #0744979 ), NIH (grants HL71626 and HL606

Studies of transketolase abnormality in Alzheimer\u27s disease / Kwan-Fu Rex Sheu, PhD; Donald D. Clarke, PhD; Young-Tai Kim, PhD; John P. Blass, MD, PhD; Bradford J. Harding; Joseph DeCicco

The partially purified transketolase from each of eight well-nourished patients with Alzheimer\u27s disease contained significantly less heat-stable component with a significantly longer half-life of heat inactivation than that from eight controls. Immunochemical studies utilizing antibodies to the purified human liver transketolase did not distinguish between red blood cell transketolases of patients with Alzheimer\u27s disease and those of controls. However, three brains from patients with Alzheimer\u27s disease that were deficient in transketolase activity lacked a 69-kilodalton form on immunoblots. Subtle structural abnormalities of transketolase appear to occur in a high proportion of patients with Alzheimer\u27s diseas