1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride Neurotoxicity Is Attenuated in Mice Overexpressing Bcl-2

Yang, Le; Matthews, Russell T.; Schulz, Jörg B.; Klockgether, Thomas; Liao, Andrew; Martinou, Jean‐Claude; Penney, John B.; Hyman, Bradley T.; Beal, M. Flint

doi:10.1523/jneurosci.18-20-08145.1998

Cited by 183 publications

(86 citation statements)

References 60 publications

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“…Consistent with these observations, Bax null and Bcl-2 transgenic mice are both resistant to MPTP neurotoxicity [19,75,76]. Bcl-2 overexpression has been shown to prevent cell death [75][76][77], probably by inhibiting Bax translocation and insertion into mitochondrial membrane, or via a direct interaction with the channels [78]. Consistent with that result, MPTP lesion can also increase the level of phosphorylated Bcl-2 and decrease the interaction of Bcl-2 with Bax.…”

Section: Discussionsupporting

confidence: 66%

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

Hacioglu

Seval-Celik

Tanrıöver

et al. 2012

Folia Histochem Cytobiol.

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Docosahexaenoic acid (DHA), a major polyunsaturated fatty acid (PUFA) in the phospholipid fraction of the brain, is essential for normal cellular function. Neurodegenerative disorders such as Parkinson's disease (PD) often exhibit significant declines in PUFAs. The aim of this study was to observe the effects of DHA supplementation in an experimental rat model of PD created with '1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine' (MPTP). Adult male Wistar rats were divided into four groups: (1) Control; (2) DHA-treated; (3) MPTP-induced; and (4) MPTP-induced + DHA-treated. Motor activity was investigated using the 'vertical pole' and 'vertical wire' tests. The dopaminergic lesion was determined by immunohistochemical analysis for tyrosine hydroxylase (TH)-immunopositive cells in substantia nigra (SN). Immunoreactivities of Bcl-2, Akt and phosphorylated-Akt (p-Akt) in SN were evaluated by immunohistochemistry. MPTP-induced animals exhibited decreased locomotor activity, motor coordination and loss of equilibrium. Diminished Parkinsonism symptoms and decreased dopaminergic neuron death were detected in the MPTP-induced + DHA-treated group compared to the MPTP-induced group. Moderate decreases in Akt staining were found in the MPTP-induced and MPTP-induced + DHA-treated groups compared to controls. p-Akt immunoreactivity decreased dramatically in the MPTP-induced group compared to the control; however, it was increased in the MPTP-induced + DHA--treated group compared to the MPTP-induced group. The staining intensity for Bcl-2 decreased prominently in the MPTP-induced group compared to the control, while it was stronger in the MPTP-induced + DHA-treated group compared to the MPTP-induced group. In conclusion, DHA significantly protects dopaminergic neurons against cell death in an experimental PD model. Akt/p-Akt and Bcl-2 pathways are related to this protective effect

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Section: Discussionsupporting

confidence: 66%

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

Hacioglu

Seval-Celik

Tanrıöver

et al. 2012

Folia Histochem Cytobiol.

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“…Taken together, our data suggest that, after MPTP administration, a cascade of deleterious events is set in motion within which Bax up-regulation and Bcl-2 down-regulation are key factors. Consistent with this scenario, the observed neuroprotective effects provided by Bcl-2 overexpression against MPTP (35,36) may reflect its capacity to counter Bax.…”

Section: Discussionmentioning

confidence: 60%

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Vila

Jackson‐Lewis

Vukosavic

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

332

253

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the proapoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease. P arkinson's disease (PD) is a common neurodegenerative disorder whose cardinal clinical features include tremor, slowness of movement, stiffness, and postural instability (1). These disabling symptoms are primarily due to a profound deficit in striatal dopamine content that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the consequent loss of their projecting nerve fibers in the striatum (2, 3). Although several approved drugs do alleviate PD symptoms, their chronic use often is associated with debilitating side effects (4), and none seem to dampen the progression of the disease. Moreover, the development of effective neuroprotective therapies is impeded by our limited knowledge of the mechanism by which SNpc dopaminergic neurons die in PD. Thus far, however, significant insights into the pathogenesis of PD have been achieved by the use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which replicates in humans and nonhuman primates a severe and irreversible PD-like syndrome (5). In several mammalian species, MPTP reproduces most of the biochemical and pathological hallmarks of PD, including the dramatic degeneration of dopaminergic neurons (5).Mounting evidence indicates that highly regulated cell deathassociated molecular pathways could participate in the relentless demise of neurons in degenerative diseases (6, 7), including PD (8). In keeping with this, Bax (9) has emerged as a pro-cell death driving force within the central decision point constituted by the Bcl-2 family that modulates the activation of downstream effectors of cell death such as caspases (7). It is also clear that Bax is required for the death of several types of neurons in the peripheral and central nervous systems during both normal development and pathological situations (10-18). In light of its critical role within the programmed cell death machinery and its importance in neuronal death, Bax appears as a particularly appealing target for therapeutic interventions aimed at hampering neurodegeneration. Consistent with a potential pivotal role for Bax in SNpc neuronal death, here we show that Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neu...

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“…Bcl-2 preventing BAX-induced release of cytochrome c from the mitochondria, the maintenance of mitochondrial function is also likely to help explain the protein's capacity to protect against necrotic cell death ( Kane et al 1993;Papadopoulos et al 1998;Yang et al 1998). This involvement of Bcl-2 in mitochondrial function has also prompted explorations of its Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These other actions include Bcl-2 enhancing mitochondrial calcium uptake and decreasing nuclear calcium accumulation (Marin et al 1996), forming ion channels in mitochondria (Green and Reed 1998), and causing the translocation of kinases to mitochondria . Moreover, Bcl-2 is capable of blocking instances of necrotic, as well as apoptotic cell death (Kane et al 1993, in neural cell lines; Yang et al 1998, in the substantia nigra; Papadopoulos et al 1998, in cortical astrocytes).…”

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confidence: 99%

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Howard

Bottino

Brooke

et al. 2002

Journal of Neurochemistry

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Overexpression of bcl-2 protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride Neurotoxicity Is Attenuated in Mice Overexpressing Bcl-2

Cited by 183 publications

References 60 publications

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

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