Deprenyl induces GFAP immunoreactivity in the intact and injured dopaminergic nigrostriatal system but fails to counteract axotomy-induced degenerative changes

Revuelta, M. P.; Venero, José L.; Machado, Alberto; Cano, Josefina

doi:10.1002/(sici)1098-1136(199710)21:2<204::aid-glia4>3.0.co;2-6

Cited by 13 publications

(6 citation statements)

References 45 publications

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“…In this regard, whereas several MAO‐B inhibitors (including l ‐deprenyl) are reported to diminish GFAP expression in C6 glioma cells (Li et al, 1993), other authors support the idea that the MAO‐B inhibitor l ‐deprenyl increases GFAP immunoreactivity after injury in the rat brain (Biagini et al, 1993). Additionally, other reports suggest that, regardless of this l ‐deprenyl‐induced increase in GFAP immunoreactivity, l ‐deprenyl failed to counteract axotomy‐induced nigrostriatal degeneration (Revuelta et al, 1997). These data suggest that understanding the role of MAO‐B inhibitors in regulating astrocytic reactivity requires further study.…”

Section: Discussionmentioning

confidence: 96%

“…Furthermore, it has also been suggested that MAO‐B inhibitors may directly regulate astrocyte reactivity, although results seem to be controversial. Although some authors report that deprenyl increases the density of reactive astrocytes as assessed by glial fibrillary acidic protein (GFAP) immunoreactivity (Biagini et al, 1993; Revuelta et al, 1997), others suggest that deprenyl and other MAO‐B inhibitors decrease GFAP expression (Li et al, 1993). Hence, the potential usefulness of MAO‐B inhibitors in regulating astrocytic response must be clarified.…”

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confidence: 99%

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Monoamine oxidase‐B activity is not involved in the neuroinflammatory response elicited by a focal freeze brain injury

Sanz

Quintana

Valente

et al. 2008

J of Neuroscience Research

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Cryolesion of the frontoparietal cortex in mice is a well-described brain injury paradigm that results in increased astrogliosis surrounding the lesion site and is accompanied by a prominent increase in the MAO-B levels in astrocytes. Whether these increased MAO-B levels contribute to cellular damage or modulate reactive astrocytosis remains unclear. MAO-B activity may contribute to cellular damage, since its metabolism products are highly toxic to the cells. Additionally, it has been suggested that MAO-B inhibition may regulate astrocytic reaction. In this study, we have determined the relative contribution of MAO-B activity to the outcome following freeze injury. Freeze injury induced a prominent increase of several inflammatory markers, including ICAM, Mac-1, EB22, and GFAP. Inhibition of MAO-B activity using the selective inhibitor PF9601N did not reduce this cryolesion-induced inflammatory response. Additional data revealed that the expression of several cryolesion-induced cell death genes, such as Fas, Rip, p53, and ICE, was not reduced in PF9601N-treated mice, evidencing that MAO-B activity did not contribute to cryolesion-induced cell death. Definitive functional analysis of the mice using the ladder beam task revealed that MAO-B inhibition did not improve the cryolesion-induced motor impairment. These data strongly suggest that, although MAO-B is highly expressed in the area surrounding the lesion site, its activity does not contribute to the cellular damage or play any role in regulating astrocytic reactivity.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Monoamine oxidase‐B activity is not involved in the neuroinflammatory response elicited by a focal freeze brain injury

Sanz

Quintana

Valente

et al. 2008

J of Neuroscience Research

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“…However, some of the in vivo results suggest that selegiline protects and rescues A9 nigral neurons against oxidative stress and degeneration caused by MPP ϩ via mechanisms independent of its capacity to inhibit MAO-B enzymatic activity. Prior studies also indicated that selegiline may induce antioxidative and neurotrophic genes for enhancing neuronal survival in vivo (Carrillo et al, 1991;Vizuete et al, 1993;Kitani et al, 1994;Semkova et al, 1996;Tatton et al, 1996;Revuelta et al, 1997;Kunikowska et al, 2002). Nevertheless, it should be noted that selegiline rescues only moderately affected midbrain dopamine neurons in vivo (Wu et al, 1995).…”

Section: Selegiline Induces Trx Expression That Prevents Mppmentioning

confidence: 99%

“…It also prevents the ironcatalyzed auto-oxidation of dopamine to melanin. Furthermore, selegiline protection of brain neurons could be augmented by its unique capacity to induce Cu/ZnSOD, MnSOD, catalase, Bcl-2, GDNF, and NGF (Carrillo et al, 1991;Vizuete et al, 1993;Kitani et al, 1994;Semkova et al, 1996;Tatton et al, 1996;Revuelta et al, 1997;Kunikowska et al, 2002). Selegiline may also bind to glyceraldehyde-3-phosphate dehydrogenase, which is known to be associated with apoptotic cell death (Tatton et al, 2003).…”

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confidence: 99%

Role of the Redox Protein Thioredoxin in Cytoprotective Mechanism Evoked by (-)-Deprenyl

et al. 2005

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Through the inhibition of monoamine oxidase type B (MAO-B), (Ϫ)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP ϩ ) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP ϩ -induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP ϩ -induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP ϩ -induced cytotoxicity, we observed further that selegiline, at 1 M or less, induced Trx for protection against oxidative injury caused by MPP ϩ . The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKAsensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 M) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP ϩ -induced neurotoxicity.(Ϫ)-Deprenyl (selegiline) was originally developed in Hungary (for review, see Knoll, 2000) and pharmacologically classified as a selective monamine oxidase type B (MAO-B) inhibitor with a broad spectrum in clinical uses including antiparkinsonian and antidepressant activities (Birkmayer et al., 1983;Murphy et al., 1983). The initial use of selegiline in patients with Parkinson's disease is aimed at increasing brain dopamine levels through the inhibition of MAO-mediated oxidative deamination of dopamine during the treatment of patients with levodopa. Clinical observations imply that selegiline might have additional neuroprotective properties reflected by slowing the progression in clinical deterioration LeWitt, 1991). Subsequent clinical trials of selegiline in the DATATOP Parkinson study and in Alzheimer's dementia indicate that this elusive neuroprotective effect of...

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“…Ballabriga et al, 1997;Revuelta et al, 1997;Rothblat and Schneider, 1998;Thiffault et al, 1997;Vaglini et al, 1996). Ballabriga et al, 1997;Revuelta et al, 1997;Rothblat and Schneider, 1998;Thiffault et al, 1997;Vaglini et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Advances in Research on Neurodegeneration

2000

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Deprenyl induces GFAP immunoreactivity in the intact and injured dopaminergic nigrostriatal system but fails to counteract axotomy-induced degenerative changes

Cited by 13 publications

References 45 publications

Monoamine oxidase‐B activity is not involved in the neuroinflammatory response elicited by a focal freeze brain injury

Monoamine oxidase‐B activity is not involved in the neuroinflammatory response elicited by a focal freeze brain injury

Role of the Redox Protein Thioredoxin in Cytoprotective Mechanism Evoked by (-)-Deprenyl

Advances in Research on Neurodegeneration

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