Hi to recent posters.
For the sake of simplicity a long time ago I mentioned that MPL is a fourth generation rapalog of Rapamycin. It isn't, but it sort of is if you look on a base level. No one but myself has called any drug a 4th generation rapalog.
So yes, I am to blame.
At the time when the scientific HC discussion was developing it seemed best to compare Rapamycin to MPL as it's difficult to compare MPL to others because it's in its own class.
So to recap and redefine;
mtor rapalogs such as Rapamycin Temsirolimus and Everolimus are inhibitors of mTORC1. They have limitations including partial mTOR inhibition, leading to modest efficacy in certain cancers. The problem identified is homeostasis feedback loops between mTORC1 and AKT ( glucose metabolism/ apoptosis/ cell proliferation/ transcription and cell migration ) thus reducing effectiveness.
MPL is an novel inhibitor of mTOR which encompasses mTORC1 and mTORC2 and is also called a mTOR kinase inhibitor, so MPL has a much broader definition of action.
I believe this is how MPL works in ALS MND , but I am only going on the evidence I have found over the years. Its 10/10 heavy duty I pre warn you.
My thoughts:A simplified summary of CNS glucose metabolism, and commonly observed defects in amyotrophic lateral sclerosis (ALS). Glucose enters into neurons via glucose transporter (GLUT3) and via GLUT1 into astrocytes. The astrocyte foot process is shown by wrapping around the capillary. Then, glucose is phosphorylated by hexokinase (HK) to glucose 6-phosphate (G6P). G6P can be converted by glucose 6-phosphate dehydrogenase (G6PDH) to 6-phospho gluconolactone to enter the pentose phosphate pathway (PPP), where it is converted by a series of enzymatic reactions to subsequent PPP intermediates, such as R5P (ribose 5-phosphate) which later can enter the glycolytic pathway via glyceraldehyde 3-phosphate (G3P) or provide nucleotide backbones. G6P may also be converted to glucose 1-phosphate which is utilized for glycogen synthesis. If G6P continues through glycolysis, it is converted into F6P (fructose 6 phosphate) and later to fructose 1,6-bisphosphate (F16BP) by phosphofructokinase (PFK). F16BP is further metabolised to glyceraldehyde 3-phosphate (G3P), phosphoenol pyruvate (PEP) and pyruvate, by a series of enzymatic processes including pyruvate kinase (PK) which converts PEP into pyruvate. Pyruvate can be reduced to lactate by lactate dehydrogenase or enters mitochondria via mitochondrial pyruvate carrier (MPC) and gets converted into acetyl CoA by pyruvate dehydrogenase (PDH). Acetyl-CoA condenses with oxaloacetate to citrate and thereby enters the tricarboxylic acid (TCA) cycle. The TCA cycle generates different TCA cycle intermediates, including α-ketoglutarate (α-KG) from which glutamate can be synthesized. During neurotransmission, glutamate is released from the presynaptic vesicles into the synapse where it is taken up by glutamate transporters in astrocytes and then converted into glutamine (Gln) by glutamine synthetase (GS). Gln can also be transferred into neurons and gets converted into Glu by phosphate activated glutaminase (PAG), completing the Glu-Gln shuttle. In **Aergic neurons, Glu is converted into **A by glutamate decarboxylase (GAD) enzyme. The TCA cycle also generates reducing equivalents such as nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide, which transfer electrons to oxygen via the enzyme complexes of the electron transport chain, ultimately resulting in the generation of ATP. In ALS, numerous metabolic defects at various steps in the glucose metabolism pathway that alter glucose metabolism and overall ATP generation have been described. This include impairments in glucose transport (changes in glucose transporter expression or HK activities), glycolysis (reduced activities of pyruvate kinase and phosphoglycerate kinase, reduced levels of lactate and reduced activities of PK), and PPP (reduced activities of G6PDH and reduced levels of R5P), increased glycogen accumulation, reduced entry of pyruvate into the TCA cycle (increased protein levels of PDH kinase 1, which downregulates PDH activity; reduced activities of oxoglutarate dehydrogenase (OGDH)), mitochondrial dysfunction, reduced mitochondrial ATP production, increased reactive oxygen species (ROS) production, as well as abnormal neuronal-glial interactions (reduced transfer of glutamate to glutamine, and glutamate excitotoxicity)Thus in layman's terms we have reduced ATP/ADP ratio in the axons. What is very strange is that MPL reduces ATP . The bodies cells need an increased ATP/ADP ratio to survive via the adenylate kinase reaction. If the ratio is skewed towards ADP it causes a glycolysis effect on the axons. The increased glycolysis increases ATP.Most of the earlier studies were done in small number of patients, and studies with larger numbers of patients with ALS have also shown similar glucose hypometabolism in frontal areas and hypermetabolism in the midbrain and cerebellum .The locomotion in a TDP-43 Drosophila model, suggesting that glycolysis activators could slow disease progression and prolong survival in ALS.Pyruvate, the end product of glycolysis, is a fuel for OXPHOS. Under aerobic conditions pyruvate enters the mitochondria to be oxidized to acetyl CoA which combines with oxaloacetate to start the tricarboxylic acid (TCA) cycle and OXPHOS, which can produce 36 ATPs.Reduced OXPHOS markers are evident in MND ALS.
Maybe why people can't understand the mechanism of Monepantel yet.
Kpax
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