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)

Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue sparing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.
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PMID:Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. 1522 38

Many central nervous system (CNS) diseases display sexual dimorphism. Exposure to circulating sex steroids is felt to be a chief contributor to this phenomenon; however, CNS diseases of childhood and the elderly also demonstrate gender predominance and/or a sexually dimorphic response to therapies. Here we show that XY and XX neurons cultured separately are differentially susceptible to various cytotoxic agents and treatments. XY neurons were more sensitive to nitrosative stress and excitotoxicity versus XX neurons. In contrast, XX neurons were more sensitive to etoposide- and staurosporine-induced apoptosis versus XY neurons. The responses to specific therapies were also sexually dimorphic. Moreover, gender proclivity in programmed cell death pathway was observed. After cytotoxic challenge, programmed cell death proceeded predominately via an apoptosis-inducing factor-dependent pathway in XY neurons versus a cytochrome c-dependent pathway in XX neurons. This gender-dependent susceptibility is related to the incapacity of XY neurons to maintain intracellular levels of reduced glutathione. In vivo studies further demonstrated an incapacity for male, but not female, 17-day-old rats to maintain reduced glutathione levels within cerebral cortex acutely after an 8-min asphyxial cardiac arrest. This gender difference in sensitivity to cytotoxic agents may be generalized to nonneuronal cells, as splenocytes from male and female 16-18-day-old rats show similar gender-dependent responses to nitrosative stress and staurosporine-induced apoptosis. These data support gender stratification in the evaluation of mechanisms and treatment of CNS disease, particularly those where glutathione may play a role in detoxification, such as Parkinson's disease, traumatic brain injury, and conditions producing cerebral ischemia, and may apply to non-CNS diseases as well.
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PMID:Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway. 1523 82

Protein misfolding has been shown to be the direct cause of a number of highly devastating diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob syndrome, affecting the aging population globally. The deposition in tissues of amyloid fibrils is a characteristic of all these diseases, and the mechanisms by which these protein aggregates form continue to be intensively investigated. In only a fraction of cases is an underlying mutation responsible, and accordingly, what initiates amyloid formation in vivo is the major question that is addressed. In this study, we show that membranes containing phosphatidylserine (PS), a negatively charged phospholipid, induce a rapid formation of fibers by a variety of proteins, viz., lysozyme, insulin, glyceraldehyde-3-phosphate dehydrogenase, myoglobin, transthyretin, cytochrome c, histone H1, and alpha-lactalbumin. Congo red staining of these fibers yields the characteristic light green birefringence of amyloid, and fluorescent lipid tracers further reveal them to include phospholipids. Our results suggest that PS as well as other acidic phospholipids could provide the physiological low-pH environment on cellular membranes, enhancing protein fibril formation in vivo. Interestingly, all the proteins mentioned above either are cytotoxic or induce apoptosis. PS-protein interaction could be involved in the mechanism of cytotoxicity of the aggregated protein fibrils, perturbing membrane functions. Importantly, our results suggest that this process induced by acidic phospholipids may provide an unprecedented and generic connection between three current major areas of research: (i) mechanism(s) triggering amyloid formation, (ii) cytotoxicity of amyloidal protein aggregates, and (iii) mechanism(s) of action of cytotoxic proteins.
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PMID:Formation of amyloid fibers triggered by phosphatidylserine-containing membranes. 1530 28

Proteasomal dysfunction may play a role in a number of neurodegenerative conditions, and in particular Parkinson's disease (PD) and related Lewy body (LB) diseases. Application of proteasomal inhibitors to neuronal cell culture systems is associated with survival-promoting effects or with cell death depending on the model system. We have applied pharmacological proteasomal inhibitors to cultured neonatal mouse sympathetic neurons in order to investigate whether these catecholaminergic neurons, which are affected in PD, are sensitive to proteasomal inhibition and, if so, which cell death pathway is activated. We report here that proteasomal inhibition leads to apoptotic death of mouse sympathetic neurons. This death is accompanied by caspase 3 activation and cytochrome c release from the mitochondria and is abrogated by caspase inhibition. Bax deletion prevented both cytochrome c release and caspase 3 activation, and also provided complete protection against proteasomal inhibition-induced death. Bcl-2 overexpression achieved a similar survival-promoting effect. There was no change in Bax levels following proteasomal inhibition, suggesting that Bax itself is not regulated by the proteasome in this cell culture system, and that a primary increase in Bax is unlikely to account for death. In contrast, levels of the BH3-only protein, Bim, increased with proteasomal inhibition. We conclude that proteasomal inhibition of mouse sympathetic neurons activates the intrinsic apoptotic pathway involving bcl-2 family members and the mitochondria.
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PMID:Application of proteasomal inhibitors to mouse sympathetic neurons activates the intrinsic apoptotic pathway. 1534 34

Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N -methyl-D-aspartate (NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.
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PMID:Deadly conversations: nuclear-mitochondrial cross-talk. 1537 59

Trichloroethylene, a common industrial solvent and a metabolic precursor of chloral hydrate, occurs widely in the environment. Chloral hydrate, which is also used as a hypnotic, has been found to condense spontaneously with tryptamine, in vivo, to give rise to a highly unpolar 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) that has a structural analogy to the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Earlier studies have revealed the relative permeability of the molecule through the blood-brain barrier and its ability to induce Parkinson-like symptoms in rats. In this study, we report that TaClo induces an apoptotic pathway in the human neuroblastoma cell line, SK-N-SH, involving the translocation of mitochondrial cytochrome c to the cytosol and activation of caspase 3. TaClo-induced apoptosis shows considerable differences from that mediated by other Parkinson-inducing agents such as MPTP, rotenone and manganese. Although it is not clear if the clinically administered dosage of chloral hydrate or the relatively high environmental levels of trichloroethylene could lead to an onset of Parkinson's disease, the spontaneous in vivo formation of TaClo and its pro-apoptotic properties, as shown in this report, should be considered.
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PMID:1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline-induced apoptosis in the human neuroblastoma cell line SK-N-SH. 1544 60

Alpha-synuclein is the main component of the intracellular protein aggregates in neurons of patients with Parkinson's disease. The occurrence of the disease is associated with oxidative damage. Although it is known that peroxidative chemistry leads to the aggregation of alpha-synuclein in vitro, the specific amino acid types of alpha-synuclein involved in this type of aggregation have not been identified. We show, using human cytochrome c plus H(2)O(2) as the source oxidative stress, that the tyrosines of alpha-synuclein are required for aggregation. The studies reveal the chemical basis for a crucial step in the aggregation process.
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PMID:Peroxidative aggregation of alpha-synuclein requires tyrosines. 1545 41

Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca(2+) channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP(+) showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP(+). MPP(+)-induced alpha-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP(+) was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP(+) neurotoxicity, which was partially dependent on external Ca(2+). Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP(+) treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents.
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PMID:TRPC1-mediated inhibition of 1-methyl-4-phenylpyridinium ion neurotoxicity in human SH-SY5Y neuroblastoma cells. 1554 11

We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 microm) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.
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PMID:Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. 1556 51

Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn induces dopaminergic neuronal cell death remains unclear. In the present study, we sought to investigate the key downstream apoptotic cell signaling events that contribute to Mn-induced cell death in mesencephalic dopaminergic neuronal (N27) cells. Mn exposure induced a dose-dependent increase in neuronal cell death in N27 cells. The cell death was accompanied by sequential activation of mitochondrial-dependent proapoptotic events, including cytochrome c release, caspase-3 activation, and DNA fragmentation, but not caspase-8 activation, indicating that the mitochondrial-dependent apoptotic cascade primarily triggers Mn-induced apoptosis. Notably, Mn treatment proteolytically activated protein kinase Cdelta (PKCdelta), a member of a novel class of protein kinase C. The caspase-3 specific inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK) significantly blocked PKCdelta cleavage and its kinase activity, indicating that caspase-3 mediates the proteolytic activation. Cotreatment with the PKCdelta inhibitor rottlerin or the caspase-3 inhibitor Z-DEVD-FMK almost completely blocked Mn-induced DNA fragmentation. Additionally, N27 cells expressing a catalytically inactive PKCdelta(K376R) protein (PKCdelta dominant negative mutant) or a caspase cleavage resistant PKCdelta(D327A) protein (PKCdelta cleavage resistant mutant) were found to be resistant to Mn-induced apoptosis. To further establish the proapoptotic role of PKCdelta, RNA interference-mediated gene knockdown was performed. Small interfering RNA suppression of PKCdelta expression protected N27 cells from Mn-induced apoptotic cell death. Collectively, these results suggest that caspase-3-dependent proteolytic activation of PKCdelta plays a key role in Mn-induced apoptotic cell death.
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PMID:Protein kinase Cdelta is a key downstream mediator of manganese-induced apoptosis in dopaminergic neuronal cells. 1560 81


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