Saturday, 15 October 2016

Asthma drug for Remyelination

Ou Z, Sun Y, Lin L, You N, Liu X, Li H, Ma Y, Cao L, Han Y, Liu M, Deng Y, Yao L, Lu QR, Chen Y.
J Neurosci. 2016 Oct 12;36(41):10560-10573


Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination; however, the underlying molecular mechanisms remain unclear. Here, we performed genome occupancy analysis by chromatin immunoprecipitation sequencing in oligodendrocytes in response to lysolecithin-induced injury and found that Olig2 and its downstream target Gpr17 are critical factors in regulating oligodendrocyte survival. After injury to oligodendrocytes, Olig2 was significantly upregulated and transcriptionally targeted the Gpr17 locus. Gpr17 activation inhibited oligodendrocyte survival by reducing the intracellular cAMP level and inducing expression of a protein kinase A signaling pathway and the transcription factor c-Fos mediated the regulatory effects of Gpr17 in oligodendrocytes. We showed that Gpr17 inhibition elevated Epac1 expression and promoted oligodendrocyte differentiation. The loss of Gpr17, either globally or specifically in oligodendrocytes, led to an earlier onset of remyelination after myelin injury in mice. Similarly, pharmacological inhibition of Gpr17 with pranlukast promoted remyelination. Our findings indicate that Gpr17, an Olig2 transcriptional target, is activated after injury to oligodendrocytes and that targeted inhibition of Gpr17 promotes oligodendrocyte remyelination.

SIGNIFICANCE STATEMENT:

Genome occupancy analysis of oligodendrocytes in response to lysolecithin-mediated demyelination injury revealed that Olig2 and its downstream target Gpr17 are part of regulatory circuitry critical for oligodendrocyte survival. Gpr17 inhibits oligodendrocyte survival through activation of Xaf1 and cell differentiation by reducing Epac1 expression. The loss of Gpr17 in mice led to precocious myelination and an earlier onset of remyelination after demyelination. Pharmacological inhibition of Gpr17 promoted remyelination, highlighting the potential for Gpr17-targeted therapeutic approaches in demyelination diseases.


Uracil nucleotide/cysteinyl leukotriene receptor is a G protein-coupled receptor that in humans is encoded by GPR17.

GPR17 is highly expressed in certain precursors of oligodendrocytes in the nerve tissue of the (CNS); it is overexpressed in CNS tissues experiencing demyelination injuries; within 48 hours of the latter types of injuries, GPR17 expression is induced in dying neurons within and on the borders of injury, in infiltrating microglia and macrophages, and in activated oligodendrocyte precursor cells.

Studies focusing on nerve tissue indicate that GPR17 is: a) highly expressed in precursors to mature oligodendrocytes but not expressed in mature oligodendrocytes, suggesting that GPR17 must be down-regulated in order for precursor cells to proceed to terminal oligodendrocyte differentiation; b) activated by uridine, Uridine diphosphate (UDP) andUDP-glucose to stimulate outward K+ channels and the aforementioned maturation responses in oligodenrocyte precursor cells; c) also activated by LTC4 and LTD4; d) more highly expressed in (CNS) tissues of animal models undergoing EAE and focal demyelination as well as in the CNS tissues of humans in MS; e) expressed in injured neurons and acts to reduce the extent of spinal cord injury f) acts to elevate neurogenesis.

Studies suggest that GPR17 is a sensor of damage in the CNS and participates in the resolution of this damage by clearing and/or promoting the re-myelination of injured neurons caused by a variety of insults perhaps including old age.

In this study they show that GPR17 promotes oligodendrocyte survival and dos this by a number of intracellular factors that I haven't got time to discuss, but look them up at your leisure if interested. However, the bottom line is that they come up with an agent pranlukast, which as its name suggests i.e. ending is ast indicates it is an asthma drug, to promote remyelination.

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly tos montelukast (Singulair). These have a function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

Will this make it... We can add it to the increasing list of potential remyelination drugs.

2 comments:

  1. Nice. Most of these drugs have pretty modest effects but are already approved for human use. (Many are OTC and seem to work differently, even!) When will we see cocktail efforts by Big Pharma?

    ReplyDelete
  2. Yet again. Can we question MS registries for that?

    ReplyDelete

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