Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism

Sagi, Yotam; Mandel, Silvia; Amit, Tamar; Youdim, Moussa B. H.

doi:10.1016/j.nbd.2006.07.020

Cited by 117 publications

(101 citation statements)

References 53 publications

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“…However, the mechanism of action of 6-OHDA differs from that of MPTP, and so inhibition of MAO-B is unlikely to affect 6-OHDA toxicity. Nevertheless, when MAO-B inhibitors are sub-chronically administered neurorestorative and neuroprotective effects are observed (Blandini et al, 2004;Sagi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

et al. 2012

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a b s t r a c tNeuronal nitric oxide synthase (nNOS) is involved in the regulation of diverse intracellular messenger systems in the brain. Nitric Oxide (NO) contributes to inducing signaling cascades that involve a complex pattern of phosphorylation of DARPP-32 (in Thr-34), which controls the phosphoproteins involved in neuronal activation. However, the role of NO in the pathophysiology of Parkinson's disease (PD) and its effect in striatal neurons have been scarcely explored. In the present work, we investigate the effects of a nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI) in the nigrostriatal pathway of striatal 6-hydroxydopamine (6-OHDA) lesioned rats. Our quantitative histological findings show that treatment with 7-NI significantly reduced 6-OHDA-induced dopaminergic damage in the dorsolateral striatum and Substantia Nigra pars compacta (SNpc). Moreover, 6-OHDA lesioned rats show a significant increase of nNOS þ and Phospho-Thr34-DARPP-32 þ cells, accompanied by a consequent decrease of total DARPP-32 þ cells, which suggests an imbalance of NO activity in the DA-depleted striatum, which is also reflected in behavioral studies. Importantly, these effects are reverted in the group treated with 7-NI. These results show a clear link between the state of phosphorylation of DARPP-32 and parkinsonism, which is regulated by nNOS. This new evidence suggests a prominent role for nitric oxide in the neurotransmitter balance within the basal ganglia in the pathophysiology of experimental parkinsonism.

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Section: Discussionmentioning

confidence: 99%

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

et al. 2012

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“…207,208 Protection in model systems might also relate to the capacity of the drug to induce upregulation of trophic factors, such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, and to activate the PI3K/AKT signaling pathway. 209 Recent studies have demonstrated that the rasagiline metabolite aminoindan exerts protective effects that might also contribute to the benefits provided by rasagiline. 210 To test for a possible neuroprotective effect in patients with PD, a novel study design, the "delayed start," was used in an attempt to avoid the confounding symptomatic effects seen with other clinical trial designs 211 (figure 8).…”

Section: Apoptosismentioning

confidence: 99%

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Olanow¹,

Stern²,

Sethi³

2009

Neurology

768

658

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Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches. 1 PD is the second most common neurodegenerative disorder, with an average age at onset of about 60 years. An estimated 5 million people throughout the world have PD, with 1 million individuals each in the United States and in Europe with the disorder. PD affects approximately 0.3% of the population and 1% to 2% of those older than 60 years.2 With the aging of the population and the substantial increase in the number of at-risk individuals older than 60 years, it is anticipated that the prevalence of PD will increase dramatically in the coming decades.

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“…Unlike neuroprotective therapeutic strategies, neurorescue or neurorestorative therapies aim to eliminate neuronal deficits and degeneration after impairment onset. Previous studies have reported that MAO-B inhibitors can facilitate the availability of neurotrophic factors (NTFs) in vitro, particularly glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) (13,14) and have demonstrated that these outcomes have neurorestorative effects (15,16). However, to our knowledge, there have been no investigations assessing the possible neurorestorative effects of selegiline on was placed at one end of the runway.…”

Section: Introductionmentioning

confidence: 99%

Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease

Zhao

Cai²

2013

International Journal of Molecular Medicine

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Abstract. The monoamine oxidase type-B (MAO-B) inhibitor, selegiline, is often recommended as a first-line treatment for Parkinson's disease (PD) and has been shwon to possess neuroprotective effects. The aim of the present study was to determine whether selegiline increases the levels of the neurotrophic factors (NTFs), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), and whether it rescues motor dysfunction and the loss of dopaminergic neurons in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced lesions. We found that the oral administration of selegiline (1.0 mg/kg/day for 14 days) successfully suppressed the MPTP-induced reduction of nigral dopaminergic neurons and striatal fibers (192.68 and 162.76% of MPTP-exposed animals, respectively; both P<0.001). Moreover, improvements in gait dysfunction were observed after 7 and 14 days of a low dose of selegiline that is reported not to inhibit MAO-B. Furthermore, there was a significant increase in GDNF and BDNF mRNA (2.10 and 2.75-fold) and protein levels (143.53 and 157.05%) in the selegiline-treated mice compared with the saline-treated MPTP-exposed mice. In addition, the Bax/Bcl-2 gene and protein expression ratios were significantly increased in the MPTP-exposed mice, and this effect was reversed by selegiline. Correlation analysis revealed that gait measurement and GDNF/BDNF levels positively correlated with the number of dopaminergic neurons. These findings demonstrate that selegiline has neurorescue effects that are possibly associated with the induction of NTFs and anti-apoptotic genes.

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Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism

Cited by 117 publications

References 53 publications

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

7-Nitroindazole down-regulates dopamine/DARPP-32 signaling in neostriatal neurons in a rat model of Parkinson's disease

The scientific and clinical basis for the treatment of Parkinson disease (2009)

Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease

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