1,721,224 research outputs found
Transgenic Mouse Models of Parkinson's Disease and Huntington's Disease
No full textParkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Another neurodegenerative disorder, Huntington's disease (HD), is characterized by striking movement abnormalities and the loss of medium-sized spiny neurons in the striatum. Current medications only provide symptomatic relief and fail to halt the death of neurons in these disorders. A major hurdle in the development of neuroprotective therapies is due to limited understanding of disease processes leading to the death of neurons. The etiology of dopaminergic neuronal demise in PD is elusive, but a combination of genetic and environmental factors seems to play a critical role. The majority of PD cases are sporadic; however, the discovery of genes linked to rare familial forms of disease and studies from experimental animal models has provided crucial insights into molecular mechanisms of disease pathogenesis. HD, on the other hand, is one of the few neurodegenerative diseases with a known genetic cause, namely an expanded CAG repeat mutation, extending a polyglutamine tract in the huntingtin protein. One of the most important advances in HD research has been the generation of various mouse models that enable the exploration of early pathological, molecular, and cellular abnormalities produced by the mutation. In addition, these models for both HD and PD have made possible the testing of different pharmacological approaches to delay the onset or slow the progression of disease. This article will provide an overview of the genetics underlying PD and HD, the animal models developed, and their potential utility to the study of disease pathophysiology
Physiological and pharmacological bases for the diverse properties of benzodiazepines and their congeners.
No full textBenzodiazepines (BZs), which have been marketed by pharmaceutical companies since the sixties, are the most commonly prescribed psychotropic drugs. Diazepam, the prototype of this class of drugs, has a vast spectrum of therapeutic indications. It possesses, over a narrow dose-range, the well-known neuropsychopharmacological profile consisting of anxiolytic, anticonvulsant, sedative, and muscle relaxant effects, and CNS depression. Recently, BZ ligands that retain anxiolytic and antiepileptic properties at doses that are unable to produce a CNS depression have been developed. The pharmacological profiles of these drugs are discussed in light of: the heterogeneity of the structure of the GABAA receptor complex; intrinsic efficacy of the ligand; action of the BZ ligand on the mitochondrial BZ receptor
P2X7 receptors as a transducer in the co-occurrence of neurological/psychiatric and cardiovascular disorders: a hypothesis
No full textBackground. Over-stimulation of the purinergic P2X(7) receptor may bring about cellular dysfunction and injury in settings of neurodegeneration, chronic inflammation, as well as in psychiatric and cardiovascular diseases. Here we speculate how P2X(7) receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders. Presentation. We hypothesize that proinflammatory cytokines, in particular interleukin-1beta, are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X(7) receptor in triggering a rise in these cytokines. Given the broad distribution of P2X(7) receptors in nervous, immune, and vascular tissue cells, this receptor is proposed as central in linking the nervous, immune, and cardiovascular systems. Testing. Investigate, retrospectively, whether a bidirectional link can be established between illnesses with a proinflammatory component (e.g., inflammatory and chronic neuropathic pain) and cardiovascular disease, for example, hypertension, and whether patients treated with anti-inflammatory drugs have a lower incidence of disease complications. Positive outcome would indicate a prospective study to evaluate therapeutic efficacy of P2X(7) receptor antagonists. Implications. It should be stressed that sufficient direct evidence does not exist at present supporting our hypothesis. However, a positive outcome would encourage the further development of P2X(7) receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders
Basic benzanilides with local anaesthetic activity
No full textFour groups of three isomers structurally related to lidocaine through the vinilogy principle are described and their pharmacological properties evaluated. The new products were obtained introducing an aromatic ring between carbamidic and N-disubstituted aminomethyl groups of the glycinamide chain. This modification allowed the basic group may be located alternatively in the ortho, meta, and para position of the aromatic ring. The ortho isomers were more toxic than the other ones. The evaluation of the local anesthetic potency through surface, infiltration and conduction tests has shown a strict activity-toxicity correlation in each group of isomers. Finally their different potency has been related to the vinilogy principle and to the receptor model of local anaesthetics
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