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Anti-Inflammatory Effects of L-Type Voltage Dependent Calcium Channel and Ryanodine Receptor Antago.

Discussion in 'Other Health News and Research' started by pattismith, Dec 30, 2017.

  1. pattismith

    pattismith Senior Member

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    Differential Neuroprotective and Anti-Inflammatory Effects of L-Type Voltage Dependent Calcium Channel and Ryanodine Receptor Antagonists in the Substantia Nigra and Locus Coeruleus

    First Online: 16 October 2014

    Abstract

    Neuroinflammation and degeneration of catecholaminergic brainstem nuclei occur early in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

    Neuroinflammation increases levels of pro-inflammatory cytokines and reactive oxygen species which can alter neuronal calcium (Ca+2) homoeostasis via L-type voltage dependent calcium channels (L-VDCCs) and ryanodine receptors (RyRs).

    Alterations in Ca+2 channel activity in the SN and LC can lead to disruption of normal pacemaking activity in these areas, contributing to behavioral deficits.

    Here, we utilized an in vivo model of chronic neuroinflammation: rats were infused intraventricularly with a continuous small dose (0.25 μg/h) of lipopolysaccharide (LPS) or artificial cerebrospinal fluid (aCSF) for 28 days.

    Rats were treated with either the L-VDCC antagonist nimodipine or the RyR antagonist dantrolene.

    LPS-infused rats had significant motor deficits in the accelerating rotarod task as well as abnormal behavioral agitation in the forced swim task and open field. Corresponding with these behavioral deficits, LPS-infused rats also had significant increases in microglia activation and loss of tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra pars compacta (SNpc) and locus coeruleus (LC).
    Treatment with nimodipine or dantrolene normalized LPS-induced abnormalities in the rotarod and forced swim, restored the number of TH-immunoreactive cells in the LC, and significantly reduced microglia activation in the SNpc.
    Only nimodipine significantly reduced microglia activation in the LC, and neither drug increased TH immunoreactivity in the SNpc.
    These findings demonstrate that the Ca+2 dysregulation in the LC and SN brainstem nuclei is differentially altered by chronic neuroinflammation. Overall, targeting Ca + 2 dysregulation may be an important target for ameliorating neurodegeneration in the SNpc and LC.

    @Hip

     
    Last edited: Dec 30, 2017
    ljimbo423, shannah and ErdemX like this.
  2. Hip

    Hip Senior Member

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    You might want to put that in normal text, as too much bold text makes it hard to read for ME/CFS patients with neurological issues. Bold works better when used to highlight a word or short phrase.
     
  3. pattismith

    pattismith Senior Member

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    I hope you can read it better like this ;)
    I thought you may be interesting by this modulatory effect on cellular calcium channels that is able to reverse LPS induced microglial activation.

    Nimodipine has already shown it could help some ME patient, could it be via this kind of microglial inhibition?
     
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  4. Hip

    Hip Senior Member

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    That's much better thanks. I have a lot trouble reading, as the virus which triggered my ME/CFS also caused a brain infection, which led to ADHD as well as brain fog, making reading hard work.


    You could well be right that the benefits that some ME/CFS patients get from nimodipine may arise from its microglial activation inhibition.

    I have just added nimodipine to my list of microglial activation inhibitors. The trouble with that list though is that many of the studies are in vitro studies, not in vivo like the above nimodipine study.

    With in vitro studies, they use a certain concentration of the drug or supplement in a cell line to achieve microglial inhibition. But that concentration may be too high to achieve in the body when the drug or supplement is taken orally.
     
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  5. pattismith

    pattismith Senior Member

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    :thumbsup:

    This US team has published several papers on the neurologic protective effect of calcium channels modulators like Nimodipine and Dantrolene.

    They put emphasis on both L type voltage calcium channels and Ryanodine receptors calcium channels:


    Calcium dysregulation via L-type voltage-dependent calcium channels and ryanodine receptors underlies memory deficits and synaptic dysfunction during chronic neuroinflammation

    Differential rescue of spatial memory deficits in aged rats by L-type voltage-dependent calcium channel and ryanodine receptor antagonism

    Blockade of L-type voltage dependent calcium channels or ryanodine receptors during chronic neuroinflammation improves spatial memory and reduces expression of inflammatory markers


    it's interesting to notice that Ryanodine Receptor calcium channels are present in neurologic system as well as cardiac muscle (RyR2) and squelettal muscle (RyR1) and that Dantrolene is able to inhibit all the RyR types.

    Dantrolene is a muscle relaxant punctually used to prevent Malignant Hyperthermia but it may have some other interests (depends mostly on the side effects that could limit it's use).

    However, the neurologic anti-inflammatory effect of these two drugs is not the only interesting finding:
    A2017 rat study about synergic activity of Nimodipine and Dantrolene on Cerebral Vasospasm showed sme promising results:

    In contrast, the combination of these drugs reduced the PHE-induced contraction by 81% in CT, but only by 69% in diabetic rats.
    . Our results suggest that the combination of dantrolene and nimodipine may have beneficial effects in both diabetics and non-diabetics with CVSP by decreasing arterial tone more than either drug alone.
     
  6. Hip

    Hip Senior Member

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    I think with microglial activation inhibitors, even if these do help, you will only get a limited success if there is an ongoing viral infection in the brain, which autopsy studies suggest is present in ME/CFS. Because microglial activation may be necessary to keep the viral infection in check in the brain.

    A better approach may be to try to limit the problems that microglial activation cause. For example, microglial activation pumps out a lot of glutamate, which is an excitatory neurotransmitter that may be responsible for the "wired" over-aroused feeling that ME/CFS patients often have. I have thread about how to tackle high glutamate:

    Five ways to reduce your ME/CFS "wired but tired" hyperaroused brain state
     
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  7. pattismith

    pattismith Senior Member

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    probably in that case, removing the virus would be the most efficient solution attacking the root...
    on the other hand, if microglial activation produces glutamate toxicity, we would expect microglial inhibition is a good target, furthermore this in vitro study shows that these two drugs not only inhibit microglial activity but also protect against glutamate toxicity:

    "dantrolene was found to be effective in preventing glutamate toxicity in cerebellar cultures of rat pups. The protective effect of dantrolene potentialized in combination with nimodipine at all doses tested. The most effective dose of dantrolene was found to be 10−4M in combination with nimodipine. As a result, both extracellular and internal calcium stores play important roles in the genesis of neuronal cell death induced by glutamate."

    And what do you think about the brain vasodilator synergic effect of Nimopidine and Dantrolene I have quoted before, it could be of interest for some ME people, especially those who are worst under brain vasoconstrictors (caffeine for example)?
     
    Last edited: Dec 30, 2017
  8. Hip

    Hip Senior Member

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    It might be, but some people have trouble with adapting to nimodipine; they have to start with low doses, and build up slowly. There are some threads about nimodipine.
     
  9. pattismith

    pattismith Senior Member

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    https://www.ncbi.nlm.nih.gov/pubmed/21541760

    Idebenone inhibition of glutamate release from rat cerebral cortex nerve endings by suppression of voltage-dependent calcium influx and protein kinase A.
    2011
    Abstract
    The present study was aimed at investigating the effect and the possible mechanism of idebenone on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Idebenone inhibited the release of glutamate that was evoked by exposing synaptosomes to the K(+) channel blocker 4-aminopyridine (4-AP), and this phenomenon was concentration dependent. Inhibition of glutamate release by idebenone was prevented by chelating extracellular Ca(2+), or by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to DL-threo-beta-benzyl-oxyaspartate, a glutamate transporter inhibitor. Idebenone decreased the depolarization-induced increase in the cytosolic free Ca(2+) concentration ([Ca(2+)](C)),whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization.

    The inhibitory effect of idebenone on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels
    , but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange.

    Furthermore, the idebenone effect on 4-AP-evoked Ca(2+) influx and glutamate release was completely abolished by the protein kinase A (PKA) inhibitors, H89 and KT5720. On the basis of these results, it was concluded that idebenone inhibits glutamate release from rat cortical synaptosomes and this effect is linked to a decrease in [Ca(2+)](C) contributed by Ca(2+) entry through presynaptic voltage-dependent Ca(2+) channels and to the suppression of PKA signaling cascade.
     

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