Browsing Department of Pharmacology and Toxicology: Faculty Research and Presentations by Title
Now showing items 8-10 of 10
RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension.Pulmonary arterial hypertension (PAH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling as well as inflammation. Rho-kinases (ROCKs) are one of the best-described effectors of the small G-protein RhoA, and ROCKs are involved in a variety of cellular functions including muscle cell contraction, proliferation and vascular inflammation through inhibition of myosin light chain phosphatase and activation of downstream mediators. A plethora of evidence in animal models suggests that heightened RhoA/ROCK signaling is important in the pathogenesis of pulmonary hypertension by causing enhanced constriction and remodeling of the pulmonary vasculature. Both animal and clinical studies suggest that ROCK inhibitors are effective for treatment of severe PAH with minimal risk, which supports the premise that ROCKs are important therapeutic targets in pulmonary hypertension and that ROCK inhibitors are a promising new class of drugs for this devastating disease.
The role of RhoA/Rho kinase pathway in endothelial dysfunctionEndothelial dysfunction is a key event in the development of vascular disease, and it precedes clinically obvious vascular pathology. Abnormal activation of the RhoA/Rho kinase (ROCK) pathway has been found to elevate vascular tone through unbalancing the production of vasodilating and vasoconstricting substances. Inhibition of the RhoA/ROCK pathway can prevent endothelial dysfunction in a variety of pathological conditions. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of the ROCK pathway and its roles in endothelial dysfunction.
Role of the central cholinergic system in the therapeutics of schizophrenia.The therapeutic agents currently used to treat schizophrenia effectively improve psychotic symptoms; however, they are limited by adverse effects and poor efficacy when negative symptoms of the illness and cognitive dysfunction are considered. While optimal pharmacotherapy would directly target the neuropathology of schizophrenia neither the underlying neurobiological substrates of the behavioral symptoms nor the cognitive deficits have been clearly established. Abnormalities in the neurotransmitters dopamine, serotonin, glutamate, and GABA are commonly implicated in schizophrenia; however, it is not uncommon for alterations in the brain cholinergic system (e.g., choline acetyltransferase, nicotinic and muscarinic acetylcholine receptors) to also be reported. Further, there is now considerable evidence in the animal literature to suggest that both first and second generation antipsychotics (when administered chronically) can alter the levels of several cholinergic markers in the brain as well as impair memory-related task performance. Given the well-established importance of central cholinergic neurons to information processing and cognition, it is important that cholinergic function in schizophrenia be further elucidated and that the mechanisms of the chronic effects of antipsychotic drugs on this important neurotransmitter system be identified. A better understanding of these mechanisms would be expected to facilitate optimal treatment strategies for schizophrenia as well as the identification of novel therapeutic targets. In this review, the following topics are discussed: 1) the central cholinergic system in schizophrenia 2) effects of antipsychotic drugs on central cholinergic neurons 3) important neurotrophins in schizophrenia, especially those that support central cholinergic neurons; 4) novel strategies to optimize the therapeutics of schizophrenia via the use of cholinergic compounds as primary (i.e., antipsychotic) treatments as well as adjunctive, pro-cognitive agents.