Neurodegeneration and neuroprotection in Parkinson disease

Fahn, Stanley; Sulzer, David

doi:10.1602/neurorx.1.1.139

Cited by 218 publications

(88 citation statements)

References 152 publications

(25 reference statements)

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“…Thus, to the extent that oxidative metabolism of endogenous DA may play a role in human PD (reviewed in ref. 25), 6OHDA may model this process. Second, among models of PD associated with SN DA neuron death, intrastriatal 6OHDA has been demonstrated unequivocally to induce apoptosis (26).…”

Section: Discussionmentioning

confidence: 99%

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Ries

Henchcliffe²,

Kareva³

et al. 2006

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

154

160

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Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.apoptosis ͉ dopamine ͉ neurotrophic ͉ programmed cell death ͉ substantia nigra

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Section: Discussionmentioning

confidence: 99%

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Ries

Henchcliffe²,

Kareva³

et al. 2006

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

154

160

View full text Add to dashboard Cite

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“…While a variety of neurons die during the course of Parkinson's disease (PD) (Sulzer and Surmeier, 2013), the sensorimotor deficits associated with the disease are attributed to the death of dopamine (DA) neurons of the substantia nigra (SN) (Fahn and Sulzer, 2004), as demonstrated by the efficacy of treatment by the DA precursor, l -3,4-dihydroxyphenlalanine ( l -DOPA) (Birkmayer and Hornykiewicz, 1961) and by D2-class DA receptor (D2-R) agonists. DA replacement therapies can however trigger excessive behavioral responses to environmental stimuli (Weintraub and Nirenberg, 2013) including dyskinesias (Fahn, 2005) and impulse control disorders (Voon et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior

et al. 2015

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Summary Modulation of corticostriatal synaptic activity by dopamine is required for normal sensorimotor behaviors. After loss of nigrostriatal dopamine axons in Parkinson's disease, l-DOPA and dopamine D2-like receptor agonists are used as replacement therapy, although these drugs also trigger sensitized sensorimotor responses including dyskinesias and impulse control disorders. In mice, we lesioned dopamine projections to left dorsal striatum and assayed unilateral sensorimotor deficits with the corridor test as well as presynaptic corticostriatal activity with the synaptic vesicle probe, FM1-43. Sham-lesioned mice acquired food equivalently on both sides, while D2 receptor activation filtered the less active corticostriatal terminals, a response that required coincident co-activation of mGlu-R5 metabotropic glutamate and CB1 endocannabinoid receptors. Lesioned mice did not acquire food from their right, but overused that side following treatment with l-DOPA. Synaptic filtering on the lesioned side was abolished by either l-DOPA or a D2 receptor agonist, but when combined with a CB1 receptor antagonist, l-DOPA or D2 agonists normalized both synaptic filtering and behavior. Thus, high-pass filtering of corticostriatal synapses by the coordinated activation of D2, mGlu-R5, and CB1 receptors is required for normal sensorimotor response to environmental cues.

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“…Parkinson's disease (PD) is a consequence of specific progressive neurodegeneration of substantia nigra (SN) pars compacta dopaminergic neurons, with the ensuing diminution of dopamine (DA) levels in the striatum and SN, accompanied by an increase in the number of glial cells, the disappearance of neuromelanin and appearance of intracytoplasmic eosinophilic inclusions-Lewy bodies which consist of aggregates of a-synuclein (Fahn and Sulzer 2004). Although the cause of neurodegeneration of SN neurons is unknown, several factors such as, e.g., environmental toxins, genetic factors, mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of PD (Fahn and Sulzer 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Although the cause of neurodegeneration of SN neurons is unknown, several factors such as, e.g., environmental toxins, genetic factors, mitochondrial dysfunction and oxidative stress play an important role in the pathogenesis of PD (Fahn and Sulzer 2004). The role of oxidative stress, which is regarded as the main factor contributing to the etiology of PD, has been a matter of paramount interest (Halliwell 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The role of oxidative stress, which is regarded as the main factor contributing to the etiology of PD, has been a matter of paramount interest (Halliwell 2006). SN cells appear to be particularly susceptible, due to presence of a high amount of DA and neuromelanin-bound iron, or a lower expression of vesicular monoamine transporter-2 (VMAT2) (Fahn and Sulzer 2004). DA is normally deaminated by monoamine oxidase (MAO), which results in the production of 3,4-dihydroxyphenylacetic acid (DOPAC) and hydrogen peroxide.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Adenosine A2A Receptor Antagonists on l-DOPA-Induced Hydroxyl Radical Formation in Rat Striatum

et al. 2009

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A(2A) adenosine receptor antagonists have been proposed as a new therapy for Parkinson's disease (PD). Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on L: -3,4-dihydroxyphenylalanine (L: -DOPA)-induced hydroxyl radical generation using in vivo microdialysis in the striatum of freely moving rats. L: -DOPA (100 mg/kg; in the presence of benserazide, 50 mg/kg) given acutely or repeatedly for 14 days generated a high level of hydroxyl radicals, measured by HPLC with electrochemical detection, as the product of their reaction with p-hydroxybenzoic acid (PBA). CSC (1 mg/kg) and ZM 241385 (3 mg/kg) decreased haloperidol (0.5 mg/kg)-induced catalepsy, while at low doses of 0.1 and 0.3 mg/kg, respectively, they did not display an effect. CSC (1 and 5 mg/kg) and ZM 241385 (3 and 9 mg/kg) given acutely, or CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly, increased the production of hydroxyl radicals in dialysates from rat striatum. Both acute and repeated administration of CSC (0.1 and 1 mg/kg) and ZM 241385 (3 mg/kg) decreased L: -DOPA-induced generation of hydroxyl radicals. However, a high single dose of either CSC (5 mg/kg) and ZM 241385 (9 mg/kg) markedly potentiated the effect of L: -DOPA on hydroxyl radical production. The increase in hydroxyl radical production by acute and chronic injection of CSC and ZM 241385 may be related to the increased release of dopamine (DA) and its metabolism in striatal dialysates. Similarly, increased DA release following a single high dose of CSC or ZM 241385 appears to be responsible for augmentation of L: -DOPA-induced hydroxyl radical formation. Conversely, the inhibition of L: -DOPA-induced production of hydroxyl radical by single and repeated low doses of CSC or repeated low doses of ZM 241385 may be related to reduced DA metabolism. Summing up, A(2A) antagonists, used as a supplement of L: -DOPA therapy, depending on the dose used, may have a beneficial or adverse effect on ongoing neurodegenerative processes and accompanying oxidative stress.

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Neurodegeneration and neuroprotection in Parkinson disease

Cited by 218 publications

References 152 publications

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Dopamine-dependent corticostriatal synaptic filtering regulates sensorimotor behavior

Effect of Adenosine A2A Receptor Antagonists on l-DOPA-Induced Hydroxyl Radical Formation in Rat Striatum

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