(Abstract) Harnessing integrated stress response for treatment of MS

[agate]

From PubMed, February 14, 2016:

Only registered and activated users can see links., Click Here To Register... 2016 Feb 9. pii: S1474-4422(15)00381-6. doi: 10.1016/S1474-4422(15)00381-6.

Harnessing the integrated stress response for the treatment of multiple sclerosis.

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Multiple sclerosis is a chronic demyelinating autoimmune disease of the CNS with no known cure. Although 12 immunomodulatory therapies exist, they have only modest effects on disease progression. The field has therefore focused on the development of alternative treatment strategies, such as enhancement of remyelination and CNS repair.

Progress has been made on a third, complementary treatment approach that aims to protect oligodendrocytes--and the myelin they generate and maintain--from inflammation-mediated death by enhancing the integrated stress response.

Studies in cells and in mouse models of multiple sclerosis have shown that this innate protective pathway, which maintains proteostasis, can be harnessed effectively to protect oligodendrocytes and myelin during inflammation.

With one drug already in clinical development for patients with multiple sclerosis, and several potential therapies under investigation, modulation of the integrated stress response might become an important component of strategies to halt the progression of the disease.

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Does anyone know anything about this? What is the "one drug already in clinical development for patients with multiple sclerosis," I wonder?

[Lazarus]

This names a drug being tested: GUANABENZ??????

"Abstract• Introduction• Results• Discussion• Methods• Additional information• References• Acknowledgements• Author information• Supplementary information
Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment.
Guanabenz ????

Subject terms: Biological sciences Immunology Neuroscience
At a glance
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CompoundsAbstract• Introduction• Results• Discussion• Methods• Additional information• References• Acknowledgements• Author information• Supplementary information
Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis.

in vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment.

Subject terms: Biological sciences Immunology Neuroscience

Genes and Proteins
Genes and Proteins

In this study, we demonstrate that guanabenz protects oligodendrocytes both in vitro (in primary culture and cerebellar explants) and in vivo from IFN-γ-mediated death. Guanabenz also protects oligodendrocytes and ameliorates clinical symptoms in chronic EAE, with a concomitant decrease in the numbers of inflammatory CD4+ T cells within the CNS. Finally, treatment with guanabenz after development of clinical symptoms in relapsing-remitting EAE dampens the severity of the subsequent relapse. These data demonstrate the CNS-protective abilities during inflammation of an FDA-approved drug that enhances the ISR, a novel treatment strategy that may have potential as a therapeutic approach to treating MS.

[SuzE-Q]

I wonder if Gary has been on this already, it's a high blood pressure med?

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[SalpalSally]

The words "Limited Ability"stand out like a sore thumb here
and the other dirty word "Mice".

oh well, they're working on It, at least!

[Gary]

No I haven't even heard of this one. There is another one called Lisinopril (an ACE inhibitor). I will bring this up to my Doc next week.