Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In animal models of parkinsonism, the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine, as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron, and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake, due to loss of nerve endings, may also lead to augmented occupancy of dopamine receptors, and so constitute yet another compensatory mechanism. In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However, the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings, leading, in vivo, to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast, in a postmortem setting, dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally, it is also possible that differences may derive, in part, from dissimilar kinetic systems for handling exogenous and endogenous levodopa.
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PMID:Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism. 201 8

Nigral neurons of crab-eating monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed a peculiar configuration occasionally in mitochondria. The outer membrane of mitochondria was covered with a net of fine parallel or latticed filaments, which turned spirally about the long axis of the mitochondria. The filaments were approximately 8 nm in diameter: parallel filaments were arranged at intervals of about 13 nm from center to center; and latticed filaments intersected each other at an angle of almost 135 degrees. When mitochondria were present in groups, the intermitochondrial gap was occasionally filled with the same parallel filaments. The netted mitochondria were frequently associated with intramitochondrial abnormalities such as small floculent inclusions and disintegrated cristae. Only one or two netted mitochondria were counted in the perikaryon of one section of an injured neuron. They appeared in about one-third of mildly or moderately injured neurons in three of six MPTP-treated monkeys, and not in normal surviving and recovering neurons of treated animals, or in neurons of control animals. We consider the netted mitochondria to be a pathological configuration related to a metabolite of oxidation of MPTP, and to be different from the stubby mitochondria reported in amyotrophic lateral sclerosis (ALS) and a non-ALS case.
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PMID:Mitochondria covered with a net of parallel and latticed filaments in nigral neurons of monkeys with experimental parkinsonism. 278 41

The human neurological disorders--amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD)--share certain features: they occur in later stages of adult life; are slowly progressive; and involve specific groups of nerve cells. Different clinical syndromes result from dysfunction and death of these specific groups of neurons. In ALS, patients are weak due to disease of motor neurons in the spinal cord. The clinical features of PD, e.g. slow movements, tremor and rigidity, are attributed, in part, to degeneration of dopaminergic neurons of the substantia nigra. Impairments of cognition and memory in AD result from disease of neurons in a number of regions, including brainstem, basal forebrain, amygdala, hippocampus, and neocortex. In each of these diseases, affected neurons exhibit abnormalities of the neuronal cytoskeleton: in ALS, neurofilaments accumulate and distend proximal motor axons; in PD, nigral perikarya show Lewy bodies-intracytoplasmic inclusions containing neurofilament antigens; in AD, neurons develop neurofibrillary tangles, Hirano bodies, granulovacuolar degeneration and filament-filled neurites in plaques. Certain features of ALS, PD and AD are recapitulated in animal models, three of which are described in this review. Hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited motor neuron disease, shows many clinical and pathological features in common with ALS, including weakness, muscle atrophy, neurofilamentous swellings of proximal axons, impaired transport of neurofilament proteins, and degeneration of motor neurons. In primates, intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a parkinsonian syndrome due to injury of nigral dopaminergic neurons and associated denervation of the striatum. Finally, aged macaques exhibit memory deficits, and their cerebral cortices show senile plaques and filament-filled neurites derived from a variety of transmitter-specific populations of nerve cells. In human diseases, the causes and mechanisms leading to dysfunction and death of nerve cells are unknown. Investigators have begun using a variety of techniques derived from neurobiology to study animal models in an effort to clarify the mechanisms, evolutions, and consequences of structural-chemical abnormalities occurring in different neuronal systems implicated in human disease. Understanding such processes in these models should provide important new insights into the pathogeneses of similar processes occurring in ALS, PD and AD.
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PMID:Dysfunction and death of neurons in human degenerative neurological diseases and in animal models. 355 88

A number of neurodegenerative diseases selectively affect distinct neuronal populations, but the mechanisms responsible for selective cell vulnerability have generally remained unclear. The toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reproduces the selective degeneration of dopaminergic neurons in the substantia nigra characteristic of Parkinson's disease. The plasma membrane dopamine transporter mediates this selective toxicity through accumulation of the active metabolite N-methyl-4-phenylpyridinium (MPP+). In contrast, the vesicular amine transporter protects against this form of injury by sequestering the toxin from its primary site of action in mitochondria. Together with the identification of defects in glutamate transport from patients with amyotrophic lateral sclerosis, these observations suggest that neurotransmitter transport may have a major role in neurodegenerative disease. The recent cloning of cDNAs encoding these transport proteins will help to explore this hypothesis.
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PMID:Neural degeneration and the transport of neurotransmitters. 790 65

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
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PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87

Recent data indicate that overexpression of the enzyme Cu,Zn superoxide dismutase (SOD1) in mice confers neuroprotection against various dopamine neurotoxins like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), methamphetamine, 6-hydroxydopamine and methylenedioxymethamphetamine. In the present study we investigated whether a mutant form of SOD1 (G93A), occurring in humans affected by amyotrophic lateral sclerosis, leads to a differential vulnerability of nigrostriatal dopaminergic neurons to the chronic dopamine depletion induced by the selective neurotoxin MPTP. Our results indicate that overexpression of both wild-type and human mutant SOD1 induces comparable neuroprotective effects against striatal dopaminergic depletion.
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PMID:Resistance to striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice expressing human mutant Cu,Zn superoxide dismutase. 1204 37

The evidence for a role of apoptosis in the neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and in the more acute conditions of cerebral ischemia, traumatic brain injury (TBI), and spinal cord injury (SCI) is reviewed with regard to potential intervention by means of small antiapoptotic molecules. In addition, the available animal models for these diseases are discussed with respect to their relevance for testing small antiapoptotic molecules in the context of what is known about the apoptotic pathways involved in the diseases and the models. The principal issues related to pharmacotherapy by apoptosis inhibition, i.e., functionality of rescued neurons and potential interference with physiologically occurring apoptosis, are pointed out. Finally, the properties of a number of small antiapoptotic molecules currently under clinical investigation are summarized. It is concluded that the evidence for a role of apoptosis at present is more convincing for PD and ALS than for AD. In PD, damage to dopaminergic neurons may occur through oxidative stress and/or mitochondrial impairment and culminate in activation of an apoptotic, presumably p53-dependent cascade; some neurons experiencing energy failure may not be able to complete apoptosis, end up in necrosis and give rise to inflammatory processes. These events are reasonably well reflected in some of the PD animal models, notably those involving 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone. In sporadic ALS, an involvement of pathways involving p53 and Bcl-2 family members appears possible if not likely, but is not established. The issue is important for the development of antiapoptotic compounds for the treatment of this disease because of differential involvement of p53 in different mutant superoxide dismutase (SOD) mice. Most debated is the role of apoptosis in AD; this implies that little is known about potentially involved pathways. Moreover, there is a lack of suitable animal models for compound evaluation. Apoptosis or related phenomena are likely involved in secondary cell death in cerebral ischemia, TBI, and SCI. Most of the pertinent information comes from animal experiments, which have provided some evidence for prevention of cell death by antiapoptotic treatments, but little for functional benefit. Much remains to be done in this area to explore the potential of antiapoptotic drugs. There is a small number of antiapoptotic compounds in clinical development. With some of them, evidence for maintenance of functionality of the rescued neurons has been obtained in some animal models, and the fact that they made it to phase II studies in patients suggests that interference with physiological apoptosis is not an obligatory problem. The prospect that small antiapoptotic molecules will have an impact on the therapy of neurodegenerative diseases, and perhaps also of ischemia and trauma, is therefore judged cautiously positively.
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PMID:Prospects for antiapoptotic drug therapy of neurodegenerative diseases. 1265 69

Minocycline has been shown previously to have beneficial effects against ischemia in rats as well as neuroprotective properties against excitotoxic damage in vitro, nigral cell loss via 6-hydroxydopamine, and to prolong the life-span of transgenic mouse models of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). We investigated whether minocycline would protect against toxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that selectively destroys nigrostriatal dopaminergic (DA) neurons and produces a clinical state similar to Parkinson's disease (PD) in rodents and primates. We found that although minocycline inhibited microglial activation, it significantly exacerbated MPTP-induced damage to DA neurons. We present evidence suggesting that this effect may be due to inhibition of DA and 1-methyl-4-phenylpridium (MPP+) uptake into striatal vesicles.
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PMID:Minocycline enhances MPTP toxicity to dopaminergic neurons. 1451 57

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading components of the extracellular matrix. Recent evidence has implicated MMPs in the pathogenesis of neurodegenerative diseases as Alzheimer's disease and amyotrophic lateral sclerosis. In this study, we investigated the involvement of MMP-9 (gelatinase B) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease using zymography, immunohistochemistry, and Western blot analysis. The activity of MMP-9 was upregulated at 3 h after MPTP injection in the striatum and after 24 h in the substantia nigra. Although MMP-9 expression decreased in the striatum by 72 h, it remained elevated in the substantia nigra compared to controls up to 7 d after MPTP administration. Immunohistochemistry showed that neurons and microglia are the source of MMP-9 expression after MPTP administration to mice. Treatment with a hydroxamate-based MMP inhibitor, Ro 28-2653 significantly reduced dopamine depletion and loss of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta. MMP-9 expression as measured via zymography in the substantia nigra was reduced by the MMP inhibitor. These results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.
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PMID:Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. 1507 39

Ketogenic diet (KD) is a high-fat, low-protein and low-carbohydrate diet. It is reported that KD can provide the neuroprotection for the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD) and amyotrophic lateral sclerosis. The main clinical symptom of PD is motor dysfunction derived from the loss of dopaminergic neurons in the substantia nigra (SN) and dopamine content in the striatum subsequently. It is well known that treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice produce motor dysfunction, biochemical, and neurochemical changes remarkably similar to idiopathic PD patients. In this study, we investigated the neuroprotective and anti-inflammatory effects of KD in MPTP-treated mice. The data showed that pretreatment with KD alleviated the motor dysfunction induced by MPTP. The decrease of Nissl-staining and tyrosine hydroxylase (TH)-positive neurons induced by MPTP was inhibited in the SN. The change of dopamine was very similar to dopaminergic neurons in the SN. KD inhibited the activation of microglia induced by MPTP in the SN. The levels of proinflammatory cytokines (interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha) in the SN were also decreased and induced by MPTP. So, we concluded that KD was neuroprotective and anti-inflammatory against MPTP-neurotoxicity.
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PMID:Neuroprotective and anti-inflammatory activities of ketogenic diet on MPTP-induced neurotoxicity. 2033 81


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