At 7:40 in this video: https://www.youtube.com/watch?v=Cd5AYWX_bT4&t=1s he talks about how endocannabinoids block neurotransmitters such as glutamate. You can't see the slides which might make it more helpful but can anyone relate this is the usefulness of cannabis, especially as it relates to IDH1 mutated tumors?
I'm also trying to make sense of how ROS is thought to be related to glutamate? I thought I read that glutamate in IDH mutated tumors stops the cells from being overwhelmed by an influx of ROS and so that is why they are so glutamate hungry.
So my next thought is could a combination of cannabis and high dose vitamin c infusions, which is thought to also overwhelm the cells with ROS, be beneficial.
I have no idea if any of this makes sense. It's just overlap I'm seeing and so I thought I'd put it out there.
Maria
I guess as I read through more material what I'm learning is the High Dose Vitamin C triggers cell death through H2O2 toxicity, through use of the cells mutated iron metabolism. I read on the website that CBD can slow growth of glioma cells via ROS but the cells simply reprogram to up regulate antioxidant response genes. This process can be inhibited via ferroptosis inducing compounds, such as Erastin. However, this doesn't cross the blood brain barrier, so that's not useful. My question then becomes can ferroptosis be essentially substituted by H2O2 toxicity, as induced by high dose vitamin c. I'm having a hard time differentiating between the two and it seems researchers might also:
ReplyDelete"The specific role of iron in ferroptosis remains unclear. Ferroptosis cannot be explained by a simple increase in H202-dependent, iron-catalyzed ROS production (i.e. Fenton chemistry), as H202-induced death is distinct from RSL-induced ferroptosis (Figures 1,,2).2). Rather, our results are most consistent with one or more iron-dependent enzymes functioning as part of the core, oxidative lethal mechanism. The void created in the antioxidant defenses of the cell by the inhibition of cystine uptake by erastin may be required to unleash the activity of these enzymes. Thus, for better or worse, the aberrantly elevated levels of iron observed in some cancer cells (Pinnix et al., 2010) and pathological neuronal populations (Duce et al., 2010; Lei et al., 2012) may predispose to ferroptotic death in situations of cystine or cysteine limitation." — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367386/
And if activating the bodies' endocannabinoid receptors through the use of cannabis also limited glutamate intake, can that be beneficial? To further complicate matters could DCA be added to the cocktail to create multiple pathways blocking the cells metabolism? This would be in addition to the use of THC which also induces cell death through a number of other pathways.
Can someone please help me make sense of all of this?
I wouldn't be able to comment on the first question before reviewing the literature on the subject. I did find a good recent review (see link below), although I'm not aware of any studies looking at cannabis or endocannabinoids specifically in relation to IDHmut gliomas.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/26987641
The proposed appetite for glutamate in IDH mutant gliomas is most likely due to the overactive conversion of alpha-ketoglutarate to 2-hydroxyglutarate by the mutant IDH enzymes. Alpha-ketoglutarate in turn is a direct derivative of glutamate. So glutamate, being a common neurotransmitter, is the most abundant substrate for producing 2-hydroxyglutarate in the brain by the mutant IDH enzymes.
It is also true that IDH mutant gliomas seem to be specially vulnerable to therapies that create ROS/oxidative damage, due to the depletion of NADPH and reduced glutathione in the mutant cells.
http://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/
A new study was just published showing that 2-hydroxyglutarate, the metabolite produced in abundance by IDH-mutant gliomas mimics the activity of glumate on NMDA glutamate receptors (being a close structural analog of glutamate) and this contributes to seizure activity. In the study, an NMDA receptor antagonist blocked this increase in neuronal firing caused by 2-HG. There happens to be a clinically approved NMDA receptor antagonist called memantine.
https://www.ncbi.nlm.nih.gov/pubmed/28404805
Mutant IDH1 and seizures in patients with glioma.
https://en.wikipedia.org/wiki/Memantine
This isn't answering your questions, but I thought I'd mention it here, as its related to glutamate and glutamate receptors.
Thank you. In addition to the study above, I was referring to the cannabinoid section on the Astrocytoma website and the studies recently shared about high dose vitamin c - https://www.ncbi.nlm.nih.gov/m/pubmed/18678913/
DeleteThe study you shared on glutamate and THC seems to say yes, that glutamate can be inhibited by cannabinoids and this could be beneficial in IDH mutated glioma.
I would recommend great caution around use of cannabis during pregnancy and nursing.
ReplyDeletehttp://www.healthline.com/health-news/children-cannabis-impairs-fetal-brain-development-012814#2
Thank you, Stephen. Of course we will.
ReplyDelete