Neurotoxic effects of methamphetamine.

In Parkinson's disease, depletion of dopamine in the striatum leads to various symptoms such as tremor, rigidity and akinesia. Methamphetamine use has significantly increased in USA and around the world and there are several reports showing that its long-term use increases the risk for dopamine depletion. However, the toxic mechanisms of methamphetamine are not well understood. This study was undertaken to gain greater mechanistic understanding of the toxicity induced by methamphetamine. We evaluated the effect of methamphetamine on the generation of reactive oxygen species, mitochondrial monoamine oxidase, complex I & IV activities. Behavioral analysis evaluated the effect on catalepsy, akinesia and swim score. Neurotransmitter levels were evaluated using high pressure liquid chromatography (HPLC) electrochemical detection (ECD). Results showed that methamphetamine caused significant generation of reactive oxygen species and decreased complex I activity in the mitochondria leading to dopamine depletion in the striatum.

Methamphetamine-induced neurotoxicity: the road to Parkinson's disease.

Studies have implicated methamphetamine exposure as a contributor to the development of Parkinson's disease. There is a significant degree of striatal dopamine depletion produced by methamphetamine, which makes the toxin useful in the creation of an animal model of Parkinson's disease. Parkinson's disease is a progressive neurodegenerative disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. The immediate need is to understand the substances that increase the risk for this debilitating disorder as well as these substances'neurodegenerative mechanisms. Currently, various approaches are being taken to develop a novel and cost-effective anti-Parkinson's drug with minimal adverse effects and the added benefit of a neuroprotective effect to facilitate and improve the care of patients with Parkinson's disease. Amethamphetamine-treated animal model for Parkinson's disease can help to further the understanding of the neurodegenerative processes that target the nigrostriatal system. Studies on widely used drugs of abuse, which are also dopaminergic toxicants, may aid in understanding the etiology, pathophysiology and progression of the disease process and increase awareness of the risks involved in such drug abuse. In addition, this review evaluates the possible neuroprotective mechanisms of certain drugs against methamphetamine-induced toxicity.

Versatile effects of sildenafil: recent pharmacological applications.

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfunction, sildenafil also provides a prolonged benefit in various other diseases. Sildenafil has been shown to have a potential therapeutic efficacy for disorders related to the central nervous system and pulmonary system. In the central nervous system, it exerts its neuroprotective effects in multiple sclerosis and has a significant memory enhancing action. Sildenafil also significantly enhances neurogenesis. Several lines of evidence indicate that targeting PDE5 with sildenafil offers novel strategies in the treatment of age-related memory impairment. Guanylate cyclase/cGMP/protein kinase G pathway or glutamate/nitric oxide/cGMP pathway appears to mediate memory enhancing effects. Some of the positive cognitive features of sildenafil therapy are likely attributable to the mechanisms reviewed here. Sildenafil has been shown to reduce pulmonary hypertension and alleviate pain in animals and humans. The present review primarily focuses on the various pharmacological effects of sildenafil with regard to its influence on the nervous and pulmonary system.

Paraquat and maneb induced neurotoxicity.

Parkinson's disease is a progressive neurological disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. It is the most common of the neurodegenerative movement disorders, affecting approximately 1% of the population over age 65. Though the exact cause of the neurodegeneration is unknown, it has been shown that environmental factors can contribute to the onset of Parkinson's disease. Parkinsonian symptoms are seen following exposure to the herbicide paraquat, and the fungicide maneb. Furthermore, evidence clearly shows that neurodegeneration develops in environments where workers are co-exposed to paraquat and maneb. These neurotoxins cause a pesticide-induced loss of dopaminergic neurons, inducing a Parkinsonian phenotype. The specific mechanisms by which these environmental neurotoxins affect the nigral dopaminergic neurons are unknown. This gap in mechanistic understanding raises a need for further examination of their cytotoxic effects. Despite advances in pharmacotherapy that have improved quality of life, the mortality rate among Parkinson's disease sufferers remains largely unchanged. There is need for a proactive treatment strategy that could provide neuroprotection or neurorestoration. Since evidence has shown that environmental neurotoxins play an important role in nigral degeneration, there is obviously a need to take a closer look at such toxins since a greater understanding could aid in development of novel pharmacological agents with anti-parkinson and neuroprotective effects. In this review, we intend to examine the role of environmental toxins, namely paraquat and maneb, in the neurotoxicity that leads to dopamine depletion.