The role of nitric oxide in nicot induced muscle cell death
Abstracts
Initial Award Abstract |
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Many pathological conditions are associated with muscle weakness or atrophy. Nicotine, a predominant component of tobacco, is known to activate receptors on muscle cells ('nicotinic receptors') resulting in cell stimulation. Excessive stimulation of these receptors, however results in muscle deterioration. The over activation of muscle cells has been related to the wasting and weakness of neck and shoulder muscles. Similarly, muscle cells directly exposed to nicotine die within a relatively short time period.
The long term goal of the present grant proposal is to identify the pathways leading from nicotine exposure to muscle degeneration. Specifically, nitric oxide is known to be responsible for many biological functions ranging from regulating blood vessel relaxation thereby affecting blood pressure to inducing cell death in the brain in models of stroke. Recent evidence suggests that this gas may play a role in mediating muscle cell death from nicotine exposure as well. The proposed experiments will provide insight into such a role for nitric oxide by characterizing the effect of 'nicotinic receptor' stimulation on nitric oxide production and relating this to muscle cell death. In addition, we will conduct experiments on rats exposed to compounds, which are used in the treatment of Alzheimer's disease. These compounds also result in the over activation of these receptors and potentially cause muscle cell death. We will determine whether nitric oxide acts as an intermediate to induce cell death in this model as well. We will also investigate whether agents which block nitric oxide production can prevent muscle degeneration. Understanding these mechanisms, therefore, may provide a means for treating such muscle disorders. |
Final Report |
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Nicotine, a predominant component of tobacco, is known to activate specific receptors on muscle cells known as nicotinic receptors which result in cell stimulation. However, excessive nicotinic receptor stimulation causes muscle cell death. For example, slow channel congenital myasthenia is a disorder characterized by the wasting and weakness of neck and shoulder muscles due to genetic mutations which result in the over-activation of muscle cells. As model of such receptor induced myopathy, direct exposure of cultured muscle cells to nicotine causes cell death. The goal of this fellowship was to identify the pathways leading from nicotine exposure to muscle degeneration. Nitric oxide is known to be responsible for many biological functions ranging from regulating blood vessel relaxation thereby affecting blood pressure to inducing cell death in the brain in models of stroke. Recent evidence suggests that this gaseous molecule may play a role in mediating muscle cell death from excessive nicotinic receptor stimulation as well.
During the course of this fellowship period, we have characterized the mechanisms involved in nicotinic receptor mediated muscle cell death. Understanding these mechanisms is important because drug therapies can then be devised to alter specific steps in the degenerative process. To further elucidate the role of nitric oxide in nicotine induced muscle cell death, we have examined the effects of nicotine on cultured muscle cells from mice genetically altered to lack a specific form of the enzyme necessary to produce nitric oxide, neuronal nitric oxide synthase (nNOS). We have observed that these cells are resistant to the degenerative effects of nicotine. This finding further implicates nitric oxide as an intermediary in nicotine induced muscle cell death. In addition, exposure to acetylcholinesterase inhibitors in vivo also results in the overstimulation of nicotinic receptors thereby causing muscle degeneration. Our most recent data suggests that drugs which inhibit nitric oxide production, specifically by blocking nNOS, are capable of preventing such myopathy (Yeluashvili et al., 1999). We have further shown that the reversible acetylcholinesterase inhibitor tacrine which has been used . therapeutically to counteract the cognitive decline observed in Alzheimer's disease, also induces muscle degeneration in rats that can be attenuated by inhibiting nitric oxide production (Jeyarasasingam et al., 2000). Continued work may identify potential therapeutic agents to prevent nicotinic receptor mediated muscle degeneration from acetylcholinesterase inhibitor exposure and perhaps slow channel congenital myasthenic syndrome. |
Publications
| Nicotine partially protects dopaminergic cells from MPP+ neurotoxicity in vitro |
| Periodical: Society for Neuroscience Abstracts |
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| Authors: Jeyarasasingam G, Quik M |
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| Yr: 1999 |
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| Nicotine partially protects dopaminergic cells from MPP+ neurotoxicity in vitro |
| Periodical: Society for Neuroscience Abstracts |
Index Medicus: |
| Authors: Jeyarasasingam G, Quik M |
ABS |
| Yr: 1999 |
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Nbr: |
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