Tuesday, 23 July 2013

Statins protect oligodendrocytes from damage

Paintlia AS, Paintlia MK, Singh AK, Singh I.Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR-α-dependent mechanism. Glia. 2013. doi: 10.1002/glia.22537. [Epub ahead of print]

We earlier documented that lovastatin (LOV)-mediated inhibition of small Rho GTPases activity protects vulnerable oligodendrocytes (OLs) in mixed glial cell cultures stimulated with Th1 cytokines and in a murine model of multiple sclerosis (MS). However, the precise mechanism of OL protection remains unclear. We here employed genetic and biochemical approaches to elucidate the underlying mechanism that protects LOV treated OLs from Th1 (tumor necrosis factor-α) and Th17 (interleukin-17) cytokines toxicity in in vitro. Cytokines enhanced the reactive oxygen species (ROS) generation and mitochondrial membrane depolarization with corresponding lowering of glutathione (reduced) level in OLs and that were reverted by LOV. In addition, the expression of ROS detoxifying enzymes (catalase and superoxide-dismutase 2) and the transactivation of peroxisome proliferators-activated receptor (PPAR)-α/-β/-γ including PPAR-γ coactivator-1α were enhanced by LOV in similarly treated OLs. Interestingly, LOV-mediated inhibition of small Rho GTPases, i.e., RhoA and cdc42, and Rho-associated kinase (ROCK) activity enhanced the levels of PPAR ligands in OLs via extracellular signal regulated kinase (1/2)/p38 mitogen-activated protein kinase/cytoplasmic phospholipase 2/cyclooxygenase-2 signaling cascade activation. Small hairpin RNA transfection-based studies established that LOV mainly enhances PPAR-α and less so of PPAR-β and PPAR-γ transactivation that enhances ROS detoxifying defense in OLs. In support of this, the observed LOV-mediated protection was lacking in PPAR-α-deficient OLs exposed to cytokines. Collectively, these data provide unprecedented evidence that LOV-mediated inhibition of the Rho-ROCK signaling pathway boosts ROS detoxifying defense in OLs via PPAR-α-dependent mechanism that has implication in neurodegenerative disorders including MS
When statins were first thought to affect EAE it was either through Th1/Th2 shift or through stopping white cell migration into brain. It was consistent that they block the cholesterol producing pathway. This involves the production of isoprenoids that are used to form Rho. Rho is a factor that controls the production of molecules involved in actin the cell skeleton. Rho signals through another molecule called ROCK. In this study they suggest that statins affect oligodendrocytes.. so is this how it effects progressive MS?

5 comments:

  1. Yeah, unfortunately this week it has been reported that statins taken over years can cause breast cancer. Any thoughts on this?

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  2. All drugs have problems

    Yes sir jeremy is going to have his work cut out...to get this to MSers.

    There may be an small increased risk

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  3. Can you tell me what is the best dose of statins to take for neuro protection

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    1. Dear Jenny
      Sorry I can't. I am not a neuro

      However at present we do not have enough information to say it works and it is safe.

      The statin trial was only phase II and we need phase III data. Sorry to be a killjoy but we ask for Class I evidence for the value of statins just like we ask the same for CCSVI

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  4. There is reasonable evidence that statins conserve vitamin d by either affecting use, say in the muscles, or by affecting recycling of vitamin d. This raises blood levels but causes muscle pain and weakness in those with low vitamin d. So they may just be an expensive source of vitamin d.

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