Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that zinc may be involved in the pathogenesis of Parkinson's disease by an apoptotic pathway. However, the mechanisms underlying zinc-induced apoptosis are unknown. Previous studies showed that 6-hydroxydopamine (6-OHDA)-enhanced potassium channels are involved in apoptosis of dopaminergic neurons. Our study was designed to test whether zinc-induced apoptosis was mediated by potassium channels. First we demonstrated cell apoptosis with zinc treatment by Hoechst staining assay. The results showed that 13.38% +/- 0.6% of MES23.5 cells were apoptotic after 24 hr of incubation with 60 microM zinc sulfate. Then we observed that the tyrosine hydroxylase (TH) protein expression and the dopamine content decreased, as detected by Western blots and high-performance liquid chromatography-electrochemical detection (HPLC-ECD). We further elucidated the mechanism of cell apoptosis by using whole-cell patch clamp recording. The data demonstrated that MES23.5 cells exhibited a tetraethylammonium (TEA)-sensitive outward K(+) current with delayed rectifier characteristics. Increases of K(+) current density were recorded following the treatment with 60 microM zinc for 4-8 hr. After incubation with 20 mM TEA, the zinc-induced enhancement of K(+) currents was fully blocked. Furthermore, incubation with TEA blocked zinc-mediated caspase-3 activation and cell apoptosis. These data suggest that zinc-induced apoptosis of MES23.5 dopaminergic cells may due to the enhancement of TEA-sensitive K(+) channel activity.
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PMID:Potassium channels are involved in zinc-induced apoptosis in MES23.5 cells. 1875 20

In the central nervous system, fibroblast growth factor (FGF)-20 has been reported to act preferentially on midbrain dopaminergic neurons. It also promotes the dopaminergic differentiation of stem cells. We have analyzed the effects of FGF-20 on human embryonic stem cells (hESCs) differentiation into dopaminergic neurons. We induced neuronal differentiation of hESCs by co-culturing those with PA6 mouse stromal cells for 3 weeks. When we supplemented the culture medium with FGF-20, the number of tyrosine hydroxylase (TH)-expressing neurons increased fivefold, from 3% to 15% of the hESC-derived cells. The cultured cells also expressed other midbrain dopaminergic markers (PITX3, En1, Msx1, and Aldh1), suggesting that some had differentiated into midbrain dopaminergic neurons. We observed no effect of FGF-20 on the size of the soma area or neurite length of the TH-immunopositive neurons. Regardless of whether FGF-20 had been added or not, 17% of the hESC-derived cells expressed the pan-neuronal marker b-III-Tubulin. The proportion of proliferating cells positive for Ki-67 was also not affected by FGF-20 (7% of the hESC-derived cells). By contrast, after 3 weeks in culture FGF-20 significantly reduced the proportion of cells undergoing cell death, as revealed by immunoreactivity for cleaved caspase-8, Bcl-2 associated X protein (BAX) and cleaved caspase-3 (2.5% to 1.2% of cleaved caspase-3-positive cells out of the hESC-derived cells). Taken together, our results indicate that FGF-20 specifically increases the yield of dopaminergic neurons from hESCs grown on PA6 feeder cells and at least part of this effect is due to a reduction in cell death.
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PMID:Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells. 1895 98

The neurotoxin 6-hydroxydopamine has been widely used to model aspects of Parkinson's disease in rodents, but the mechanisms underlying toxin-induced dopaminergic degeneration and functional impairment have not been fully elucidated. The main aim of the present study was to assess a possible role for calpains in neurochemical and behavioral deficits following unilateral infusion of intrastriatal 6-hydroxydopamine in adult rats. Toxin administration produced a profound dopaminergic denervation, as indicated by a 90-95% reduction in dopamine transporter radiolabeling measured in the caudate-putamen at 2 weeks post-lesion. Treatment with 6-hydroxydopamine also resulted in calpain activation in both caudate-putamen and substantia nigra, as measured by the appearance of calpain-specific spectrin breakdown products. Calpain activation peaked at 24 h after 6-hydroxydopamine infusion and remained elevated at later time points. In contrast, caspase-3-mediated spectrin cleavage subsided within 48 h in both brain areas. In a subsequent experiment, calpain inhibition was achieved by intrastriatal infusion of an adenovirus expressing the endogenous calpain inhibitor, calpastatin. Calpastatin delivery abolished the lesion-induced calpain-mediated spectrin cleavage and alleviated forelimb asymmetries resulting from unilateral intrastriatal 6-hydroxydopamine. Unexpectedly, dopamine transporter and tyrosine hydroxylase labeling revealed significant neuroprotection, not in the nigrostriatal pathway but rather in the ventral tegmental area. These findings support a role for calpain activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. However, after near-total dopaminergic depletion, the primary benefit of calpain inhibition may not occur within the nigrostriatal dopaminergic pathway itself.
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PMID:Effects of calpain inhibition on dopaminergic markers and motor function following intrastriatal 6-hydroxydopamine administration in rats. 1900 62

Deferoxamine (DFO) and erythropoietin (EPO) have each been shown to provide neuroprotection in neonatal rodent models of brain injury. In view of the described anti-oxidative actions of DFO and the anti-apoptotic and anti-inflammatory effects of EPO, we hypothesized that the combination of DFO and EPO would increase neuroprotection after neonatal hypoxic-ischemic brain injury as compared to single DFO or EPO treatment. At postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were treated intraperitoneally with DFO (200mg/kg), recombinant human EPO (1 kU/kg), a combination of DFO-EPO or vehicle at 0, 24 and 48 h after hypoxia-ischemia (HI) and were sacrificed at 72 h. DFO-EPO administration reduced the number of cleaved caspase 3-positive cells in the ipsilateral cerebral cortex. Early neuronal damage was assessed by staining for microtubuli-associated protein (MAP)-2. In our model 63+/-9% loss of ipsilateral MAP-2 was observed after HI, indicating extensive brain injury. DFO, EPO or DFO-EPO treatment did not improve neuronal integrity as defined by MAP-2. Cerebral white matter tracts were stained for myelin basic protein (MBP), a constituent of myelin. Hypoxia-ischemia strongly reduced MBP staining which suggests white matter damage. However, DFO, EPO and DFO-EPO treatment had no effect on the loss of MBP staining. Finally, HI-induced loss of striatal tyrosine hydroxylase staining was not attenuated by DFO, EPO or DFO-EPO. Although DFO-EPO treatment reduced the number of cleaved caspase 3(+) cells, treatment with DFO, EPO, or with the combination of DFO and EPO did not protect against gray or white matter damage in the experimental setting applied.
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PMID:Combination of deferoxamine and erythropoietin: therapy for hypoxia-ischemia-induced brain injury in the neonatal rat? 1910 62

Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30% and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.
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PMID:Nifurtimox induces apoptosis of neuroblastoma cells in vitro and in vivo. 1926 45

Diadenosine tetraphosphate (AP(4)A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP(4)A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP(4)A is protective against methamphetamine (MA)-mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14-E15) ventral mesencephalic tissue. Cultures treated with 2mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP(4)A. The protective effect of AP(4)A was also found in vivo. Adult Sprague-Dawley rats were injected with AP(4)A (25 microg/20 microl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/kg), given subcutaneously every 2h. Administration of MA reduced locomotor activity 1 day after injection, which was significantly antagonized by the pretreatment with AP(4)A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP(4)A. Taken together, our data show that AP(4)A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA-induced apoptosis.
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PMID:Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration. 1944 29

Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. PD-1, a traditional Korean medicine, used to treat various brain diseases in Korea. This study was designed to investigate the effect of PD-1 extract in the Parkinson's model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned mice. The MPTP administration caused the dopamine neuron loss in the striatum and substantia nigra pars compacta (SNpc), which was demonstrated by a depletion of tyrosine hydroxylase (TH). In addition, a reduction of bcl-2 expression with elevation of bax expression, caspase-3 activation, and release of cytochrome c into cytosol in dopaminergic neurons of SNpc were noted. Oral administration of PD-1 extract (50 and 100 mg kg(-1)) attenuated the MPTP-induced depletion of TH proteins in the striatum and SNpc and prevented the apoptotic effects. These results indicate that PD-1 extract is able to protect dopaminergic neurons from MPTP-induced neuronal death, with important implications for the treatment of PD.
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PMID:Preventive role of PD-1 on MPTP-induced dopamine depletion in mice. 2018 64

Recent studies have shown that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in dopaminergic neuronal degeneration, and direct blockade of JNK by specific inhibitors may prevent or effectively slow the progression of Parkinson disease (PD). Previous studies have revealed that the natural phenolic compound curcumin can reduce inflammation and oxidation, which makes it a potential therapeutic agent for neurodegenerative diseases. In this study, we investigated whether curcumin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) or 1-methyl-4-phenylpyridnium ion- (MPP(+)) induced dopaminergic neurotoxicity in C57BL/6N mice or SH-SY5Y cells by inhibiting JNK pathways both in vivo and in vitro. Curcumin treatment significantly improved behavioral deficits, and enhanced the survival of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) in the MPTP-induced PD model mice. Most importantly, curcumin treatment significantly inhibited MPTP/MPP(+)-induced phosphorylation of JNK1/2 and c-Jun, and cleaved caspase-3. Our study suggests that the neuroprotective effect of curcumin is not related simply to its antiinflammatory and antioxidant properties, but involves other mechanisms, particularly by targeting the JNK pathways.
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PMID:Curcumin prevents dopaminergic neuronal death through inhibition of the c-Jun N-terminal kinase pathway. 2023 Feb 79

The present work was conducted to investigate the antioxidant activity and neuroprotective effects of Tripterygium regelii extract (TRE) on H(2)O(2)-induced apoptosis in human dopaminergic cells, SH-SY5Y. TRE possessed considerable amounts of phenolics (282.73 mg tannic acid equivalents/g of extract) and flavonoids (101.43 mg naringin equivalents/g of extract). IC(50) values for reducing power and DPPH radical scavenging activity were 52.51 and 47.83 microg, respectively. The H(2)O(2) scavenging capacity of TRE was found to be 57.68 microM x microg(-1) min(-1). By examining the effects of TRE on SH-SY5Y cells injured by H(2)O(2), we found that after incubation of cells with TRE prior to H(2)O(2) exposure, the H(2)O(2) induced cytotoxicity was significantly reversed and the apoptotic features such as change in cellular morphology, nuclear condensation and DNA fragmentation was inhibited. Moreover, TRE was very effective attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H(2)O(2). TRE extract effectively suppressed the up-regulation of Bax, Caspase-3 and -9, and down-regulation of Bcl-2. Moreover, TRE pretreatment evidently increased the tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. These findings demonstrate that TRE protects SH-SY5Y cells against H(2)O(2)-induced injury and antioxidant properties may account for its neuroprotective actions and suggest that TRE might potentially serve as an agent for prevention of neurodegenerative disease associated with oxidative stress.
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PMID:Antioxidant activity and protective effects of Tripterygium regelii extract on hydrogen peroxide-induced injury in human dopaminergic cells, SH-SY5Y. 2046 94

Hydrogen peroxide (H2O2) is a major Reactive Oxygen Species (ROS), which has been implicated in many neurodegenerative conditions including Parkinson's disease (PD). Rosmarinus officinalis (R. officinalis) has been reported to have various pharmacological properties including anti-oxidant activity. In this study, we investigated the neuroprotective effects of R. officinalis extract on H2O2-induced apoptosis in human dopaminergic cells, SH-SY5Y. Our results showed that H2O2-induced cytotoxicity in SH-SY5Y cells was suppressed by treatment with R. officinalis. Moreover, R. officinalis was very effective in attenuating the disruption of mitochondrial membrane potential and apoptotic cell death induced by H2O2. R. officinalis extract effectively suppressed the up-regulation of Bax, Bak, Caspase-3 and -9, and down-regulation of Bcl-2. Pretreatment with R. officinalis significantly attenuated the down-regulation of tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC) gene in SH-SY5Y cells. These findings indicate that R. officinalis is able to protect the neuronal cells against H2O2-induced injury and suggest that R. officinalis might potentially serve as an agent for prevention of several human neurodegenerative diseases caused by oxidative stress and apoptosis.
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PMID:Neuroprotective effect of Rosmarinus officinalis extract on human dopaminergic cell line, SH-SY5Y. 2056 2


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