JAK2 inhibition is neuroprotective and reduces astrogliosis after quinolinic acid striatal lesion in adult mice

Ignarro, Raffaela Silvestre; Vieira, André Schwambach; Sartori, César Renato; Langone, Francesco; Rogério, Fábio; Parada, Carlos Amílcar

doi:10.1016/j.jchemneu.2013.02.005

Cited by 27 publications

(14 citation statements)

References 56 publications

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“…A previous study demonstrated a role of Jak-2 in drug-induced damage of the striatum [22]. This study revealed that inhibition of Jak-2 reduced neuronal damage and the formation of scars after quinolinic acid treatment [22]. This model is completely unrelated to major depression, but the role of Jak-2 is analogous to that of Jak-3 in the present study.…”

Section: Discussionsupporting

confidence: 80%

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Role of Janus-Kinases in Major Depressive Disorder

Gulbins¹,

Grassmé

Hoehn

et al. 2016

Neurosignals

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Background/Aims: Major depressive disorder is a severe, common and often chronic disease with a significant mortality due to suicide. The pathogenesis of major depression is still unknown. It is assumed that a reduction of neurogenesis in the hippocampus plays an important role in the development of major depressive disorder. However, the mechanisms that control proliferation of neuronal stem cells in the hippocampus require definition. Here, we investigated the role of Janus-Kinase 3 (Jak-3) for stress-induced inhibition of neurogenesis and the induction of major depression symptoms in mice. Methods: Stress was induced by the application of glucocorticosterone. Brain sections were stained with phospho-specific antibodies and analysed by confocal microscopy to measure phosphorylation of Jak-3 specifically in the hippocampus. Jak-3 inhibitors and the antidepressant amitriptyline were applied to counteract stress. The effects of the inhibitors were determined by a set of behavioural tests and analysis of Jak-3 phosphorylation in brain sections. Acid sphingomyelinase-deficient mice were employed to test whether Jak3 is downstream of ceramide. Results: The data show that stress reduces neurogenesis, which is restored by simultaneous application of Jak-3 inhibitors. Inhibition of neurogenesis correlated with an anxious-depressive behaviour that was also normalized upon application of a Jak-3-inhibitor. Confocal microscopy data revealed that stress triggers a phosphorylation and thereby activation of Jak-3 in the hippocampus. Amitriptyline, a commonly used antidepressant that blocks the acid sphingomyelinase, or acid sphingomyelinase-deficiency reduced stress-induced phosphorylation of Jak-3. Conclusion: Our data show that Jak-3 is activated by stress at least partially via the acid sphingomyelinase and is involved in the mediation of stress-induced major depression.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 55%

Role of Janus-Kinases in Major Depressive Disorder

Gulbins¹,

Grassmé

Hoehn

et al. 2016

Neurosignals

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“…These results imply the blockade of JAK-STAT signaling and, in particular, those of JAK3 activity, as a promising therapeutic strategy to contrast the degenerative progression of ALS, especially for patient subtypes associated with aberrant activation of this pathway. In support of this theory, several studies showed neuroprotective effects of JAK inhibitors (Ignarro et al 2013). Among these, WHI-P131 treatment exhibited promising results in ALS preclinical studies, slowing disease progression and increasing survival of ALS transgenic mice (Trieu et al 2000).…”

Section: Discussionmentioning

confidence: 83%

Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

et al. 2017

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Amyotrophic lateral sclerosis (ALS) is a progressive and incurable neurodegenerative disease. Although several compounds have shown promising results in preclinical studies, their translation into clinical trials has failed. This clinical failure is likely due to the inadequacy of the animal models that do not sufficiently reflect the human disease. Therefore, it is important to optimize drug target selection by identifying those that overlap in human and mouse pathology. We have recently characterized the transcriptional profiles of motor cortex samples from sporadic ALS (SALS) patients and differentiated these into two subgroups based on differentially expressed genes, which encode 70 potential therapeutic targets. To prioritize drug target selection, we investigated their degree of conservation in superoxide dismutase 1 (SOD1) G93A transgenic mice, the most widely used ALS animal model. Interspecies comparison of our human expression data with those of eight different SOD1G93A datasets present in public repositories revealed the presence of commonly deregulated targets and related biological processes. Moreover, deregulated expression of the majority of our candidate targets occurred at the onset of the disease, offering the possibility to use them for an early and more effective diagnosis and therapy. In addition to highlighting the existence of common key drivers in human and mouse pathology, our study represents the basis for a rational preclinical drug development.Electronic supplementary materialThe online version of this article (doi:10.1007/s12031-017-0898-9) contains supplementary material, which is available to authorized users.

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“…Striatal neurogenesis following injury has been well studied (Reynolds and Weiss, 1992; Parent et al, 2002; Bédard et al, 2002; Luzatti et al, 2011; DeCaudo et al, 2012; Sun et al, 2012; Supeno et al, 2013; Ignarro et al, 2013). Although suggestions of a dormant population of striatal progenitors is controversial, Bédard et al (2002) reported a low level of neurogenesis in the normal monkey striatum thought to derive from striatal progenitors.…”

Section: Discussionmentioning

confidence: 99%

Methamphetamine Induces Low Levels of Neurogenesis in Striatal Neuron Subpopulations and Differential Motor Performance

et al. 2014

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Methamphetamine (METH) causes significant loss of some striatal projection and interneurons. Recently, our group reported on the proliferation of new cells 36 hours after METH and some of the new cells survive up to 12 weeks (Tulloch et al., 2011b). We hypothesized that some of these cells will differentiate and express striatal neuronal phenotypes. To test this hypothesis, mice were injected with METH (30mg/kg) followed by a single BrdU injection (100 mg/kg) 36 hours after METH. One week after METH, a population of BrdU-positive cells expressed the neuronal progenitor markers nestin (18%) and β-III-tubulin (30%). At 8 weeks, 14% of the BrdU-positive cells were also positive for the mature neuron marker, NeuN. At 12 weeks, approximately 7% of the BrdU-positive cells co-labeled with ChAT, PV or DARPP-32. We measured motor coordination on the rotarod and psychomotor activity in the open-field. At 12 weeks, METH–injected mice exhibited delayed motor coordination deficits. In contrast, open-field tests revealed that METH-injected mice compared to saline mice displayed psychomotor deficits at 2.5 days but not at 2 or more weeks after METH. Taken together, these data demonstrate that some of the new cells generated in the striatum differentiate and express the phenotypes of striatal neurons. However, the proportion of these new neurons is low compared to the proportion that died by apoptosis 24 hours after the METH injection. More studies are needed to determine if the new neurons are functional.

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JAK2 inhibition is neuroprotective and reduces astrogliosis after quinolinic acid striatal lesion in adult mice

Cited by 27 publications

References 56 publications

Role of Janus-Kinases in Major Depressive Disorder

Role of Janus-Kinases in Major Depressive Disorder

Selection and Prioritization of Candidate Drug Targets for Amyotrophic Lateral Sclerosis Through a Meta-Analysis Approach

Methamphetamine Induces Low Levels of Neurogenesis in Striatal Neuron Subpopulations and Differential Motor Performance

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