Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurodegenerative disorders involve death of cell bodies, axons, dendrites and synapses, but it is surprisingly difficult to determine the spatiotemporal sequence of events and the causal relationships among these events. Neuronal compartments often crucially depend upon one another for survival, and molecular defects in one compartment can trigger cellular degeneration in distant parts of the neuron. Here, we consider the novel approaches used to understand these biologically complex and technically challenging questions in amyotrophic lateral sclerosis, spinal muscular atrophy, glaucoma, Alzheimer's disease, Parkinson's disease and polyglutamine disorders. We conclude that there is partial understanding of what degenerates first and why, but that controversy remains the rule not the exception. Finally, we highlight strategies for resolving these fundamental issues.
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PMID:Neuronal death: where does the end begin? 1733 56

Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.
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PMID:Inflammatory mediators leading to protein misfolding and uncompetitive/fast off-rate drug therapy for neurodegenerative disorders. 1767 53

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.
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PMID:Cannabinoids in health and disease. 1828 1

Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.
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PMID:Calcium ions in neuronal degeneration. 1847 27

Oxidative stress occurs when the level of prooxidants exceeds the level of antioxidants in cells resulting in oxidation of cellular components and consequent loss of cellular function. Oxidative stress is implicated in wide range of age-related disorders including Alzheimer's disease, Parkinson's disease amyotrophic lateral sclerosis (ALS), Huntington's disease and the aging process itself. In the anterior segment of the eye, oxidative stress has been linked to lens cataract and glaucoma while in the posterior segment of the eye oxidative stress has been associated with macular degeneration. Key to many oxidative stress conditions are alterations in the efficiency of mitochondrial respiration resulting in superoxide (O(2)(-)) production. Superoxide production precedes subsequent reactions that form potentially more dangerous reactive oxygen species (ROS) species such as the hydroxyl radical (OH), hydrogen peroxide (H(2)O(2)) and peroxynitrite (OONO(-)). The major source of ROS in the mitochondria, and in the cell overall, is leakage of electrons from complexes I and III of the electron transport chain. It is estimated that 0.2-2% of oxygen taken up by cells is converted to ROS, through mitochondrial superoxide generation, by the mitochondria. Generation of superoxide at complexes I and III has been shown to occur at both the matrix side of the inner mitochondrial membrane and the cytosolic side of the membrane. While exogenous sources of ROS such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins may contribute to the oxidative milieu, mitochondria are perhaps the most significant contribution to ROS production affecting the aging process. In addition to producing ROS, mitochondria are also a target for ROS which in turn reduces mitochondrial efficiency and leads to the generation of more ROS in a vicious self-destructive cycle. Consequently, the mitochondria have evolved a number of antioxidant and key repair systems to limit the damaging potential of free oxygen radicals and to repair damaged proteins (Fig. 1). The aging eye appears to be at considerable risk from oxidative stress. This review will outline the potential role of mitochondrial function and redox balance in age-related eye diseases, and detail how the methionine sulfoxide reductase (Msr) protein repair system and other redox systems play key roles in the function and maintenance of the aging eye.
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PMID:Mitochondrial function and redox control in the aging eye: role of MsrA and other repair systems in cataract and macular degenerations. 1858 75

Primary open-angle glaucoma (POAG) is a pressure-sensitive optic neuropathy which results in the death of retinal ganglion cells and causes associated loss of vision. Presently, the only accepted treatment strategy is to lower the intraocular pressure; however, for some patients this is insufficient to prevent progressive disease. Although the pathogenesis of POAG remains unclear, there is considerable evidence that energy failure at the optic nerve head may be involved. Neuroprotection, a strategy which directly enhances the survival of neurons, is desirable, but remains clinically elusive. One particular form of neuroprotection involves the notion of enhancing the energy supply of neurons. These 'bioenergetic' methods of neuroprotection have proven successful in animal models of other neurodegenerative diseases and conditions, including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and traumatic brain injury, but have been relatively unexplored in glaucoma models. This review focuses on some of the potential approaches for bioenergetic neuroprotection in the retina, including increasing the energy buffering capacity of damaged cells, decreasing the permeability of the mitochondrial membrane pore and free radical scavenging.
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PMID:Bioenergetic-based neuroprotection and glaucoma. 1870 Sep 28

Neuroprotection is a therapeutic approach that aims to prevent neuronal degeneration and loss of function. Research has focused on developing neuroprotective agents for the therapy of various degenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and glaucoma. Clinical trials for the evaluation of neuroprotective agents pose unique challenges in terms of experimental design and data interpretation. In order to generate meaningful results, clinical trials on neuroprotective agents should ideally be designed to minimize the potential for bias and optimize the ability to detect the neuroprotective effect of a therapeutic intervention in as short a time as possible. Key issues for the design of clinical trials of neuroprotective therapies include identifying appropriate endpoints and determining the ideal timing of the intervention. Neuroprotection trials in glaucoma must be designed to distinguish between the neuroprotective effects of the therapy and the protective effect of intraocular pressure lowering. The choice of suitable functional endpoints in glaucoma trials is also a critical consideration. For example, visual field loss can be used as a functional endpoint; however, it occurs slowly and may require many years before meaningful changes occur. New methods for assessing visual function may be useful for assessing neuroprotective effects of therapeutic interventions. Although there have been a plethora of medications studied for neuroprotective effects in clinical trials, few have been approved by regulatory agencies for use in patients. Despite these challenges, properly designed clinical trials with validated endpoints will yield the most useful information on the neuroprotective effects of therapy, and may provide new treatment options to prevent the loss of neurologic function, including vision.
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PMID:Clinical trials in neuroprotection. 1892 19

Retinal ganglion cell axons within the globe are functionally specialized being richly provided with many mitochondria. The mitochondria produce the high energy requirement for nerve conduction in the unmyelinated part of the ganglion cell axons. We have proposed that in the initiation of glaucoma, an alteration in the quality of blood flow dynamics in the optic nerve head causes a compromise in the retinal ganglion cell axon energy requirement, rendering the ganglion cells susceptible to additional insults. One secondary insult might be light entering the eye to further affect ganglion cell axon mitochondrial function. Other insults to the ganglion cells might be substances (e.g., glutamate, nitric oxide, TNF-alpha) released from astrocytes. These effects ultimately cause ganglion cell death because of the inability of mitochondria to maintain normal function. We therefore suggest that ganglion cell apoptosis in glaucoma is both receptor and mitochondrial mediated. Agents targeted specifically at enhancing ganglion cell mitochondrial energy production should therefore be beneficial in a disease like glaucoma. Ganglion cell death in glaucoma might therefore, in principle, not be unlike the pathophysiology of numerous neurological disorders involving energy dysregulation and oxidative stress. The trigger(s) for ganglion cell apoptosis in glaucoma is/are likely to be multifactorial, and the rationale for targeting impaired energy production as a possibility of improving a patient's quality of life is based on logic derived from laboratory studies where neuronal apoptosis is shown to occur via different mechanisms. Light-induced neuronal apoptosis is likely to be more relevant to ganglion cell death in glaucoma than, for example, neuronal apoptosis associated with Parkinson's disease. Logic suggests that enhancing mitochondrial function generally will slow down ganglion cell apoptosis and therefore benefit glaucoma patients. On the basis of our laboratory studies, we suggest that supplements such as creatine, alpha-lipoic acid, nicotinamide, and epigallocatechin gallate (EGCG), all of which counteract oxidative stress induced by light and other triggers, are worthy of consideration for the treatment of such patients as they can be taken orally to reach the retina without having significant side effects.
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PMID:Pathogenesis of ganglion "cell death" in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria. 1892 20

Stem cell transplantation is currently being explored as a therapy for many neurodegenerative diseases including glaucoma. Cellular therapies have the potential to provide chronic neuroprotection after a single treatment, and early results have been encouraging in models of spinal cord injury and Parkinson's disease. Stem cells may prove ideal for use in such treatments as they can accumulate at sites of injury in the central nervous system (CNS) and may also offer the possibility of targeted treatment delivery. Numerous stem cell sources exist, with embryonic and fetal stem cells liable to be superseded by adult-derived cells as techniques to modify the potency and differentiation of somatic cells improve. Possible neuroprotective mechanisms offered by stem cell transplantation include the supply of neurotrophic factors and the modulation of matrix metalloproteinases and other components of the CNS environment to facilitate endogenous repair. Though formidable challenges remain, stem cell transplantation remains a promising therapeutic approach in glaucoma. In addition, such studies may also provide important insights relevant to other neurodegenerative diseases.
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PMID:Stem cells for neuroprotection in glaucoma. 1892 31

Apoptosis, or programmed cell death, is another example of a physiological principle of non-immune systems adopted by the immune response. Cell death by necrosis produces inflammation and disruption of surrounding tissue. Cell elimination by apoptosis is neat and allows the adjacent tissue to function; thus, apoptosis probably first emerged over 1.5 billion years ago as a means of remodeling the organism during embryogenesis.Nonetheless, apoptosis has the potential to produce inflammatory mediators. Perhaps of more concern is that abnormalities of apoptosis can lead to disruption in normal T and B cell function; in two mouse models, the result of defective apoptosis is auto-immunity. As well, the remnants of the dead cell, which essentially committed suicide, contain many nuclear components; there is reason to believe that some people may not manage this particulate waste matter, called apoptotic bodies, and that the immune response to some of these components may lead to auto-immunity. Apoptosis has also been proposed as contributing to neuronal destruction in Parkinson's disease, Alzheimer's disease, and glaucoma and to the late death of neurons near areas of ischemic cell death from stroke. Thus, not only from the rheumatologist's perspective, understanding and manipulating apoptosis may be one of the major foci of medical research of the future.
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PMID:Molecular biology and immunology for clinicians, 8 pathogenesis of autoimmunity-apoptosis. 1907 96


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