Showing papers by "Costantino Iadecola published in 2009"

NMDA receptor activation increases free radical production through nitric oxide and NOX2.

Abstract: Reactive oxygen species (ROS) and nitric oxide (NO) participate in NMDA receptor signaling. However, the source(s) of the ROS and their role in the increase in cerebral blood flow (CBF) induced by NMDA receptor activation have not been firmly established. NADPH oxidase generates ROS in neurons, but there is no direct evidence that this enzyme is present in neurons containing NMDA receptors, or that is involved in NMDA receptor-dependent ROS production and CBF increase. We addressed these questions using a combination of in vivo and in vitro approaches. We found that the CBF and ROS increases elicited by topical application of NMDA to the mouse neocortex were both dependent on neuronal NO synthase (nNOS), cGMP, and the cGMP effector kinase protein kinase G (PKG). In mice lacking the NADPH oxidase subunit NOX2, the ROS increase was not observed, but the CBF increase was still present. Electron microscopy of the neocortex revealed NOX2 immunolabeling in postsynaptic somata and dendrites that also expressed the NMDA receptor NR1 subunit and nNOS. In neuronal cultures, the NMDA-induced increase in ROS was mediated by NADPH oxidase through NO, cGMP and PKG. We conclude that NADPH oxidase in postsynaptic neurons generates ROS during NMDA receptor activation. However, NMDA receptor-derived ROS do not contribute to the CBF increase. The findings establish a NOX2-containing NADPH oxidase as a major source of ROS produced by NMDA receptor activation, and identify NO as the critical link between NMDA receptor activity and NOX2-dependent ROS production.

Threats to the Mind Aging, Amyloid, and Hypertension

Abstract: Aging, Alzheimer disease, and hypertension, major determinants of cognitive dysfunction, are associated with profound alterations in the structure and function of cerebral blood vessels. These vascular alterations may impair the delivery of energy substrates and nutrients to the active brain, and impede the clearance of potentially toxic metabolic byproducts. Reactive oxygen species derived form the enzyme NADPH oxidase are key pathogenic effectors of the cerebrovascular dysregulation. The resulting alterations in the homeostasis of the cerebral microenvironment may lead to cellular dysfunction and death and to cognitive impairment. The prominent role that cerebrovascular oxidative stress plays in conditions associated with cognitive impairment suggests new therapeutic opportunities to counteract and, possibly, reverse the devastating effects of cerebrovascular dysfunction on the brain.

The Neuroprotective Effect of Prostaglandin E2 EP1 Receptor Inhibition has a Wide Therapeutic Window, is Sustained in Time and is not Sexually Dimorphic:

Abstract: We investigated the preclinical characteristics of the neuroprotective effect of the prostaglandin E2 type 1 receptor (EP1) antagonist SC51089 in models of focal cerebral ischemia produced by occlusion of the mouse middle cerebral artery (MCA). We found that systemic administration of SC51089 (5 to 20 μg/kg; i.p.) reduces the brain injury produced by transient (−50% ± 8%; n = 12; P < 0.05) or permanent (−39% ± 7%; n = 12; P < 0.05) MCA occlusion. SC51089 was effective even when administered up to 12 h after ischemia. The protective effect was observed both in male and female mice and was sustained for at least 2 weeks after induction of ischemia. The reduction in injury volume was associated with an improvement in neurological function assessed by the Bederson deficit score, the hanging wire test and the corner test. The data provide proof of principle that EP1 receptor inhibition is a potentially valuable strategy for neuroprotection that deserves further preclinical investigation for therapeutic application in human stroke.

Cerebral vascular dysregulation in the ischemic brain

Abstract: Publisher Summary This chapter describes the cerebral vascular dysregulation in the ischemic brain. Cerebral ischemia produces profound alterations of the major control mechanisms governing the cerebral circulation. Cerebral ischemia results in a profound disruption of cerebrovascular regulatory mechanisms that assure that the brain is adequately perfused. Cerebral ischemia impairs cerebrovascular autoregulation, attenuates functional hyperemia, and alters hypercapnic vasodilation, critical mechanisms by which active brain cells maintain the homeostasis of their microenvironment through delivery of nutrients and removal of waste. These alterations are in large part mediated by a surge of free radicals, which leads to neurovascular oxidative stress and impairs the function of neurons, glia, and vascular cells. These alterations in vascular regulation render the brain more vulnerable to the changes in perfusion pressure and to the metabolic dysfunction induced by ischemia, thereby increasing the susceptibility of the tissue to injury. The introduction of techniques for measuring regional cerebral blood flow (CBF) provides new insights into the alterations of CBF distribution following focal or global cerebral ischemia. Therapeutic strategies targeting the cerebrovascular dysfunction induced by ischemia offer the opportunity to preserve postischemic vascular regulation and improve the outcome of cerebral ischemia. Such a vaso-protective approach, in combination with cytoprotective therapies, may open new avenues for the treatment of ischemic stroke.

Estrous cycle-dependent neurovascular dysfunction induced by angiotensin II in the mouse neocortex.

Abstract: Female mice are protected from the cerebrovascular dysfunction induced by angiotensin II (Ang II), an effect attributed to estrogen. We examined whether such cerebrovascular protection from Ang II is related to the estrous cycle. Cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6 female mice equipped with a cranial window. The phase of the estrous cycle was determined by vaginal smear cytology and plasma estrogen measurement. Ang II (0.25 microg/kg per minute, IV, 30 to 45 minutes) elevated arterial pressure (15 to 20 mm Hg) equally across the estrous cycle. However, in proestrus and estrus, phases in which estrogen is relatively high, Ang II did not impair the increase in the cerebral blood flow induced by neural activity or by endothelium-dependent vasodilators (P>0.05 from vehicle). In contrast, in diestrus (lower estrogen), Ang II induced a marked cerebrovascular dysfunction comparable to that of male mice. For example, the cerebral blood flow responses to whisker stimulation and to the endothelium-dependent vasodilator acetylcholine were attenuated by 41+/-12% and 49+/-12%, respectively (P 0.05 from control). Topical treatment with ICI182,780 reestablished Ang II-induced oxidative stress in proestrus (P>0.05 from diestrus). We conclude that the protection from the neurovascular dysfunction induced by acute administration of Ang II in females depends on the estrous cycle and may underlie the increased propensity to cerebrovascular damage associated with low estrogen states.

Bleeding in the brain: Killer waves of depolarization in subarachnoid bleed

Abstract: Hemorrhages in the brain are responsible for about 15% of strokes and are particularly difficult to treat. Costantino Iadecola assesses a new clinical study that may change the view of why a common form of hemorrhage, subarachnoid hemorrhage, often leads to death. Massive brain lesions often develop days after the initial event, a dangerous complication previously attributed to vasospasm, narrowing of the arteries. The study suggests that these lesions may instead by caused by neuronal depolarization, extending in waves across the brain. Gregory del Zoppo explores the connection between deposition of toxic amyloid-β peptides in the brain and hemorrhage. He discusses studies suggesting that the peptides inactivate proteins in the blood that can stop hemorrhage.

Vascular Cognitive Impairment: Small Vessels, Big Toll Introduction

Abstract: This year’s Princeton conference featured a session on vascular cognitive impairment (VCI), signaling recognition, a long time in coming, of this important consequence of cerebrovascular disease. The emphasis was on cerebrovascular dysregulation and small vessel white matter disease, drawing from animal models, human pathology, neuroimaging, epidemiology, and the recent clinical trial in CADASIL, as summarized below. Cerebrovascular oxidative stress from reactive oxygen species mediated by NADPH oxidase present in cerebral vessels may be the final common pathway of the cerebrovascular dysregulation induced by aging, Alzheimer disease (AD), and hypertension, according to Iadecola and colleagues.1 Cerebral energy demands are serviced through control mechanisms such as functional hyperemia and cerebrovascular autoregulation, which tailor the blood supply to tissue needs and maintain perfusion over a wide range of blood pressures. Aging changes the structure and vasodilatory capacity of vessels, increasing susceptibility to ischemia. Chronic hypertension induces remodeling and stenosis of the arteries and fibrinoid necrosis of the arterioles, …

Normal Responses to Restraint Stress in Mice Lacking the Gene for Neuronal Nitric Oxide Synthase

Abstract: The hormonal changes associated with immobilization stress (IMO) include a swift increase in corticosterone (CORT) concentration and a decrease in circulating testosterone (T) levels. There is evidence that the production of the short-lived neuromodulator nitric oxide (NO) is increased during stress in various tissues, including the brain. NO also suppresses the biosynthesis of T. Both the inducible and the neuronal isoforms of NO synthase (iNOS and nNOS, respectively) have been implicated in this suppression, but the evidence has not been conclusive. We used adult wild-type (WT) and nNOS knockout male mice (nNOS-/-) to assess the respective roles of CORT and nNOS-derived NO in stress mediated inhibition of T production. Animals were assigned to either basal control or 3-hour IMO groups. No difference in basal plasma and testicular T levels were observed between WT and nNOS-/-, although testicular weights of mutant mice were slightly lower compared to WT animals. The plasma contents of luteinizing hormone (LH) and CORT in unstressed mice of both genotypes were similar. Exposure to 3 hours of IMO increased plasma CORT and decreased T concentrations in mice of both genotypes. However, comparable levels of plasma LH and testicular nitrite and nitrate (NOx), NO stable metabolites, were detected in control and stressed WT and nNOS-/- mice. Adrenal concentrations of NOx declined after IMO, but the reduction was not statistically significant. These findings implicate CORT rather than NO generated by nNOS in the rapid stress-induced suppression of circulating T.

39. Brain dendritic cells in ischemic stroke

Abstract: Leukocyte activation is a hallmark of hypertension; including adhesion molecule expression, oxygen radical generation and, in animal studies, pseudopod (PP) formation. PPs are formed in locomotion and cell spreading, while blebs form when the membrane separates from the cytoskeleton, usually found during apoptosis. In this study, PP formation as well as susceptibility to bleb formation in response to the fixation protocol were evaluated. Thirteen unmedicated subjects with mildly elevated BP (SBP and/or DBP > 130/ 85 mmHg) and nine with normal BP underwent 20-min treadmill exercise (65–70% VO2peak). Whole heparinised blood collected at baseline and during the last minute of exercise was fixed within 1min with 1 formalydehyde. Following red cell lysis, cells were collected, resuspended, stained and viewed under a light microscope. One hundred cells per sample were evaluated by two observers blinded to sample and group. At baseline bleb formation was increased in subjects with elevated BP (33.1% vs. 13.4%, p = .001), but PP formation was not different. Post-exercise elevated BP neutrophils showed a trend toward greater bleb and PP formation (Blebs: 35.2% vs. 22.3%, p = .09; PPs: 3.3% vs. 0.7%, p = .07). Further, resting SBP and DBP correlated with bleb formation at baseline (r’s > 0.55; p’s < .01) and post-exercise (r’s > 0.47; p’s < .03), and with PP formation post-exercise (r’s > 0.43; p’s < .05). Elevated BP is associated with greater exercise-induced PP formation which is in line with other aspects of leukocyte activation. Neutrophils of individuals with elevated BP are also more susceptible to bleb formation by environmentally noxious stimuli.