Neuroprotective Efficacy of YM872, an ␣-Amino-3-Hydroxy-5- Methylisoxazole-4-Propionic Acid Receptor Antagonist, after Permanent Middle Cerebral Artery Occlusion in Rats

ABSTRACT The neuroprotective efficacy of YM872, a novel, highly watersoluble ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, was investigated in rats subjected to permanent occlusion of the left middle cerebral artery. The rats were assessed either histologically or neurologically 24 hr or 1 wk after ischemia. YM872 was intravenously infused for either 4 or 24 hr at dose rates of 0 to 20 mg/kg/hr starting 5 min after ischemia to examine the effect of prolonged treatment. YM872 was then infused at 20 mg/kg/hr beginning 0 to 4 hr after ischemia to determine the efficacy time window. Additionally, a 20 mg/kg/hr dose rate of YM872 was infused for 4 hr in single day-or 5-day repetitive-administrations to evaluate long-term benefits of the drug. YM872 significantly reduced infarct volume in both 4-and 24-hr treatment groups measured 24 hr after ischemia. No difference was observed in the degree of protection between length of infusion. Significant neuroprotection was maintained even when drug administration was delayed up to 2 hr after ischemia. A single YM872-administration significantly improved neurological deficit and reduced infarct volume (30%, P Ͻ .01) measured 1 wk after ischemia. YM872 treatment did not induce such adverse effects as physiological changes, serious behavioral abnormalities or nephrotoxicity. These data suggest that the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor plays a crucial role in the progression of neuronal damage in the early phase of ischemia and that YM872 may be useful in treating acute ischemic stroke

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

Prolonged Therapeutic Window for Ischemic Brain Damage Caused by Delayed Caspase Activation

Apoptotic cell death is prominent in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease? and is found in cerebral ischemia. Using a murine model of delayed cell death, we determined that cleavage of zDEVD-amino-4-trifluoromethyl coumarin (zDEVD-afc) in brain homogenate, a measure of caspase activation, increased initially 9 hours after brief (30 minutes) middle cerebral artery occlusion along with caspase-3p20 immunoreactive cleavage product as determined by immunoblotting. zDEVD-afc cleavage activity was blocked by pretreatment or posttreatment with the caspase-inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl-ketone (zDEVD-fmk), and ischemic damage was reduced when the drug was injected up to 9 hours after reperfusion. The protection was long lasting (21 days). Hence, the period before caspase activation defined the therapeutic opportunity for this neuroprotective agent after mild ischemic brain injury. Prolonged protection after caspase inhibition plus the extended treatment window may be especially relevant to the treatment of neurodegenerative disorders.WoSScopu