Cannabinoids for Amyotrophic Lateral Sclerosis (ALS)

Cannabinoids for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a motor condition that causes paralysis of the patient and subsequent death. As ALS is a disease without a cure or effective treatment, cannabinoids are presented as molecules capable of delaying symptoms while improving the quality of life of patients.

The main cause of this pathology is the progressive death of the neurons responsible for transmitting the nerve impulse to the muscles, also known as motor neurons. Found mainly in the gray matter of the spinal cord (the inner part of the spinal cord), as the death of the spinal cord increases, weakness in the extremities increases (it usually affects one type first and spreads to the other). This entails muscular atrophy that will evolve in the final stages towards total paralysis, which normally causes respiratory failure that leads to the death of the patient. In addition, during the development of the disease, there is another secondary symptomatology related to pain, lack of appetite, or lack of sleep. Buy Dank Vapes online

ALS was first described in 1869 by the French physician JM Charcot. Today it is considered a rare disease since the prevalence value reflects that there are around 2 people who suffer from it for every 100,000 inhabitants. While the condition is usually more common in men than women in a 3 to 1 ratio. Most cases are considered sporadic, around 90%, while the remaining 10% are cases of family origin, that is, that there is a genetic inheritance. From sporadic cases, studies have been carried out on environmental factors as possible causes of the disease. Pesticides, heavy metals, and even an excess of physical activity have been studied without reaching a direct relationship, as no significant differences were found in the populations studied. However, in both cases, multiple proteins and genes responsible for the triggering of ALS have been identified. In the 1990s, the first mutation that was identified was in the SOD1 protein gene, which has made it the most studied. It was not until 2006 when TDP43 was also identified as another protein whose mutation is associated with ALS. In recent years, other genes have been added to the list of involved mutations, such as FUS, or more prevalently, the gene. In the 1990s, the first mutation that was identified was in the SOD1 protein gene, which has made it the most studied.  Buy cannabis oil online

It was not until 2006 when TDP43 was also identified as another protein whose mutation is associated with ALS. In recent years, other genes have been added to the list of involved mutations, such as FUS, or more prevalently, the gene. In the 1990s, the first mutation that was identified was in the SOD1 protein gene, which has made it the most studied. It was not until 2006 when TDP43 was also identified as another protein whose mutation is associated with ALS. In recent years, other genes have been added to the list of involved mutations, such as FUS, or more prevalently, the gene.C9orf72. It should be noted that depending on which protein is involved, in addition to producing a characteristic symptom of ALS, a picture of dementia may also be reflected. In any case, most of the mutations in these genes generally produce erroneous protein folding and, consequently, functional failures that trigger the death of motor neurons. Buy Hemp Products

These events include protein aggregation as a trigger for cell death (protein malformations collapse neuronal systems causing their death); failures in cellular respiration of motor neurons that trigger oxidative stress (they are large neurons with very long axons to connect with muscles and therefore their energy expenditure is higher); excess glutamate at synapses that promote excitotoxicity (glutamate is a neurotransmitter that activates motor neurons, but excessive activation can lead to motor death); a marked glial activation associated with an increase in inflammation (by astrocytes that are the main neuronal and microglial trophic support by emulating functions of the immune system but within the central nervous system), etc.

However, the fact that for so many years there was only evidence of the mutated protein SOD1 as responsible for the disease, has hampered the study of the pathology itself and of possible drugs to treat it. Plenty of molecules and drugs have been tried with some success in preclinical trials, but when it came to jumping into the clinic and into patient trials they failed to deliver. For this reason, for years only riluzole was available as an approved drug, a molecule focused on preventing glutamate excitotoxicity, but with a scarce therapeutic window. In 2017 a second molecule was approved for the treatment of ALS, called edaravone. This compound focused on reducing oxidative stress has a better result in those cases of early diagnosis. Finally, there is the masitinib, a third compound in the absence of approval focused on mitigating glial inflammation which has had good results in preclinical and clinical trials. This situation reflects a need to find new molecules that can serve a better therapeutic response. Buy dank vapes cartridges online

Why then can cannabinoids be considered useful molecules to treat ALS? Firstly, because cannabinoids have already been proven as good therapeutic agents in other neurodegenerative diseases, examples being Alzheimer’s or Parkinson’s disease. Second, cannabinoids could have a relevant advantage over other molecules or drugs, and that is that they are molecules with a broad spectrum of action. Unlike the aforementioned drugs that focus on a single pathological aspect of the disease, cannabinoids can cope with more than one at a time. It is well known for its neuroprotective, antioxidant, anti-inflammatory qualities, etc.

However, this idea contrasts with the fact that there are few pharmacological experiments in animal models, and even less at the clinical level. In fact, the most relevant trials in patients have been carried out since 2010. Focused on the application of Δ 9 -THC only for the treatment of secondary symptoms of the disease. And to tell the truth, the expected results were not predictably obtained due to the high concentration used, since effects derived from the psychoactivity of the cannabinoid were recorded. Cannabis for sale

What exactly is known about preclinical models and experimental animal models? The use of experimental models has allowed the study of the endocannabinoid system within the disease, and as in other diseases, it has been seen that certain elements of it are altered and that we can modulate those changes in order to adapt a specific treatment.

Clarifyingly, the endocannabinoid system, like other neurotransmitter systems such as glutamate or dopamine, is made up of various receptors in different cells. The main ones are the CB1 receptor (characteristic of neurons and whose activation produces the psychoactive effects of Δ 9 -THC) and CB2 (characteristic of glial cells and mediator of inflammatory effects). These, naturally, are activated by endogenous molecules of the body (in this case, the so-called endocannabinoids), the best known being anandamide and 2AG (2 arachidonylglycerol), which are regulated by synthetic enzymes (NAPE-PLD and DAGL) and degradation (FAAH and MAGL). Cannabinoids that come from the Cannabis sativa plant such as the aforementioned Δ9- THC or CBD (cannabidiol) and act on the various elements of the endocannabinoid system, they are called phytocannabinoids. Buy cannabis oil online

Being clear about the constitution of the endocannabinoid system, most of the preclinical studies on this system within ALS have been carried out with models of mutated SOD1. The first pharmacological tests were carried out with Δ 9-THC with the idea of ​​increasing the survival of motor neurons by activating the CB1 receptors that these cells possess. Despite obtaining a certain positive effect, it has been found that the best therapeutic effects found have been mediated by the action of the CB2 receptor. This is because over the years the role of glial activation (astrocytes and microglia) has become increasingly relevant not so much as a consequence of ALS, but as a cause of it. Furthermore, in parallel, studies of the endocannabinoid system in this mutated SOD1 model reflected an increase in CB2 receptor levels.

With these two premises, pharmacological tests were performed with the synthetic cannabinoid AM-1241, selective for the CB2 receptor exclusively. Said treatment managed to significantly delay the evolution of the disease correlated with less glial activation, that is, less inflammation. Another route studied with these same positive effects was to block the degradation enzyme MAGL. When this enzyme is blocked, the levels of the endocannabinoid 2AG (2-arachidonylglycerol) increase more than normal, leading to greater activation mainly of the CB2 receptor, and somewhat less of CB1. Dank vapes for sale

Furthermore, this same CB2 receptor overexpression has been found in a new ALS model with the mutated TDP43 protein. As occurred in the SOD1 model, the same toxic events resulting from glial activation were obtained with parallel activation of the CB2 receptors of these cells. Pharmacological treatment with another selective synthetic cannabinoid, in this case, HU-308, again achieved a delay in the symptoms of the disease and greater survival of motor neurons. Which translates into mice that develop the disease later with longer survival.  CBD VAPE HARDWARE

In conclusion, based on the fact that cannabinoids have already been demonstrated as therapeutic compounds for various neurodegenerative diseases, ALS being such a disease in which a multitude of toxic events occurs, it is clear that the strategy of using direct pharmacology facing a single target is ineffective in treating it. Precisely this reason converts cannabinoids as potentially beneficial molecules for the treatment of ALS. Whether obtained from plants or synthesized in the laboratory, the information obtained from the different pharmacological tests with cannabinoids has shown that modulation of the endocannabinoid system is a reality with a positive effect. And in ELA, specifically, There is a strong basis for believing that those cannabinoids that mediate CB2 receptor activation (whose overexpression could be a marker of the disease) can help patients by delaying the symptomatology of the disease, improving quality of life and lengthening it. It only remains to put it into practice.

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