Section on Neuroendocrinology

Section on Oxidative Stress
 

The Section on Neuroendocrinology focuses on the endocannabinoid system, which is involved in the regulation of appetite and the metabolism of lipids, and is therefore implicated in obesity, alcoholism and cardiovascular disease. The Section previously provided the first evidence that mice deficient in the cannabinoid receptor CB1 showed reduced food intake following temporary food deprivation. However, the use of rimonabant (a CB1 antagonist) for obesity was abandoned due to neuropsychiatric side effects, so the Section is currently testing other CB1 antagonists with limited brain penetration. The Section is particularly interested in AM6545. It has used mouse models of obesity to show that AM6545 does not affect behavioral responses mediated by CB1 receptors in the brain, and that the compound significantly reduced weight without reducing caloric intake. The Section is currently conducting similar experiments on JD-5037, another CB1 antagonist with limited brain penetrance. The Section is also studying fatty-acid hydrolase (FAAH), an enzyme that catalyzes the degradation of the endocannabinoid anandamide. In vivo experiments with hypertensive rats have shown that AM3506 (an FAAH inhibitor) normalizes elevated blood pressure and cardiac contractility without causing hyperglycemia or insulin resistance.

The Section on Oxidative Stress – Tissue Injury focuses on the mechanisms involved in oxidative-nitrosative/nitrative stress and inflammation, which are involved in many pathological conditions. For example, the cancer drug Doxorubicin has been shown to kill cardiomyocytes and endothelial cells by producing reactive oxygen and nitrogen species. The Section has shown that peroxynitrite is a mediator of contractile dysfunction and Doxorubicin-induced cell death. The Section’s work on cardiovascular disease also involves two inflammation regulators: nuclear factor kappa B (NF-kappaB) and high-mobility group box 1 (HMGB1). This work has shown that the influence of oxidants on NF-kappaB is context-dependent, and that peroxynitrite is a key mediator of HMGB1, which seems to provide a key mechanism linking oxidative/nitrative stress and post-infarction myocardial inflammation. The Section has also examined the mechanisms involved in cell sepsis. Results from these investigations include the finding that bacterial flagellin signals TLR5, which elicits innate immune defenses and apoptotic signaling. Additionally, the Section has shown that knockout mice lacking A2B adenosine receptors are more vulnerable to bacterial sepsis and that the novel inosine analogue INO-2002 reduces sepsis by neutralizing peroxynitrite. The Section’s other work examines relationships between oxidative/nitrosative stress, inflammation and the endocannabinoid receptors CB1 and CB2. This work suggests that CB1 is a key mediator of oxidative stress and cell death in the heart, while CB2 activation decreases inflammation and tissue injury. The Section’s alcohol-related work focuses on resveratrol, the red-wine constituent thought to provide protection against cardiovascular disease. This work suggests that resveratrol induces mitochondrial biogenesis in coronary artery endothelial cells and attenuates mitochondrial oxidative stress.