Sunday, 31 January 2016

Remyelinating

Dehghan S, Hesaraki M, Soleimani M, Mirnajafi-Zadeh J, Fathollahi Y, Javan M. Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice. Neuroscience. 2016 . pii: S0306-4522(16)00047-6.

Multiple sclerosis is a demyelinating disease with severe neurological symptoms due to blockage of signal conduction in affected axons. Spontaneous remyelination via endogenous progenitors is limited and eventually fails. Recent reports showed that forced expression of some transcription factors (factors that control making proteins) within the brain converted cells  to neural progenitors and neuroblasts (cells that make nerves). Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-(toxin that kills  oligodendrocytes) induced experimental demyelination. Mice were gavaged (fed) with VPA for one week, and then inducible Oct4 expressing lentiviral particles (gene therapy vector) were injected into the lateral ventricle (fluid filled space in the brain). After one-week induction of Oct4, LPC was injected into the optic chiasm (bit where optic nerves leave the brain) . Functional remyelination was assessed by visual-evoked potential (VEP) recording. Myelination level was studied using FluoroMyelin staining and immunohistofluorescent (IHF) against proteolipid protein (PLP). IHF was also performed to detect Oct4 and SSEA1 as pluripotency markers (stem cell markers) and Olig2, Sox10, CNPase and PDGFRα as oligodendrocyte lineage markers. One week after injection of Oct4 expressing vector, pluripotency markers SSEA1 and Oct4 were detected in the rims of the ventricle. LPC injection caused extensive demyelination and significantly delayed the latency (delay) of VEP wave. Animals pre-treated with VPA+Oct4 expressing vector, showed faster recovery in the VEP latency and enhanced myelination. Immunostaining against oligodendrocyte lineage markers showed an increased number of Sox10+ and myelinating cells. Moreover, transdifferentiation of some Oct4-transfected cells (GFP+ cells) to Olig2+ and CNPase+ cells was confirmed by immunostaining. One-week administration of VPA followed by one-week forced expression of Oct4 enhanced myelination by converting transduced cells to myelinating oligodendrocytes. This finding seems promising for enhancing myelin repair within the adult brains.

So more ways to make myelin

4 comments:

  1. Valproic acid should be studied for both possible neurodegeneration and remyelination potential URGENTLY. It's mechanism of action, much like phenytoin/dilantin, possible enhances GABA and blocks Na channels, thereby blocking Na rushing in to neurons and causing cell death. Valproic acid is much better tolerated with less side effects than phenytoin. Do you know if this trial has been done or initiated by any group? There are 15 approved meds that address the inflammatory component MS and it is time to change and address neurodegeneration and remyelination. 85% of RRMS patients will be SPMS patients by 15 years and none of these 15 approved medications have been shown to address this yet.

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    1. Many drugs are better tolerated than phenytoin however it is not without its problems including dru-drug interactions. As fornews about phentoin and sodum channels news is here

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  2. MD then it is the same "valproic acid", the anticonvulsant and mood stabilizer? Valparin?

    Valproate is in the essential drug list of the WHO, as far as I know...


    If valproic acid acts by decreasing the conductance of voltage-dependent sodium channels and inhibit degradation of GABA, then Phenytoin and Carbamazepine have the same effect if associated with stimulation of transcription factor Oct4?

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    1. Yes this is possible if it is sodium doing the business but this would need to be checked

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