Cannabinoids and Neurogenesis : The Promised Solution for Neurodegeneration ?
Andrea Valeri and Emanuela Mazzon
Molecules, 2021, 26, 6313, 1-26.
doi : 10.3390/molecules26206313
Abstract : The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.
Keywords : cannabinoid receptors; neurogenesis; neuroregeneration; phytocannabinoids; synthetic cannabinoids
Neurodegeneration is primarily defined as the progressive loss of neurons, though not limited to, in the brain. . Neurodegeneration is the main hallmark and the common feature between the major neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), where resulting dementia and/or motor impairment lead inevitably to the loss of individual independence. The treatments proposed for these devastating diseases can fight one aspect of the many different causes: i.e., Aducanumab, a monoclonal antibody recently approved for AD treatment, focuses its action on reducing beta-amyloid (A) accumulation, with decreased tau phosphorylation only in a small portion of patients. Moreover, as all drugs it comes with side effects, which can be headache or dizziness, but also temporary brain swelling and bleeding were reported . AD, PD and ALS are not the only diseases that can lead to loss of neurons: vascular diseases such as ischemia and hemorrhagic stroke can occur in different brain areas, as well as infections or accidents [3–5]. For a long time, neurons were considered irreplaceable, so when trauma or injury succeeded in damaging an area of the brain, it was believed its function was lost forever. However, some observations and hypothesis theorized the presence of immature neurons or undifferentiated cells in the brain that can differentiate in neurons, and several tests proved their existence: in one of the oldest experiments, in 1965, the autoradiography of rat brains, after injection of H3-thymidine, pointing at the dentate gyrus (DG) of the hippocampus as the site of neurogenesis. Interestingly, this process, also, seemed to continue, even if to a lesser extent, in adult rats .
Cannabis sativa plants contain different chemical species and more than 60 belong to the group of terpenophenolic compounds of cannabinoids . The beneficial properties of C. Sativa are not a mystery, since historians found evidence of the use of this plant several centuries before Christ as painkiller or in shamanic rituals . Cannabinoids that can be extracted directly from the plant fall under the name of phytocannabinoids, where D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major and most famous: THC is known for being psychoactive, while CBD does not possess any psychotropic effect and therefore, it represents a better candidate for medical use . It is possible to extract cannabinoids from the plant using different methods: the organic solvent method is the first of the conventional ones, but the use of heat and acids may provoke modifications in the desired compound; the supercritical fluid extraction often use the CO2 and a co-solvent, in order to overcome the inability of CO2 to dissolve polar compounds. The supercritical fluid extraction is also reported as method to obtain a high yield of non-psychoactive compounds for C. Sativa; the other methods are dynamic maceration, ultrasound-assisted
extraction and microwave-assisted extraction .
The potential applications of CBD, and cannabinoids more in general, in the treatment of several diseases, think anti-inflammatory , immunomodulatory  and neuroprotective properties , lead to the synthesis of artificial cannabinoids compounds, named synthetic cannabinoids. To date, Food and Drug Administration (FDA) approved four different drugs based on cannabinoids and two of them contain synthetic cannabinoids: Cesamed or Nabilone, whose formula recalls THC one  and Marinol or Dronabinol , a synthetic THC. The other two drugs are Epidiolex, also approved in Europe, based on plant-extracted CBD  and Sativex, composed of THC and CBD in a proportion 1:1 . Since 1945 cannabinoids gain more and more attention, but only after the beginning of the new millennia the studies and PubMed publications regarding cannabinoids highly increased, from 379 in 2000 to 2473 in 2020. Cannabinoids and neurogenesis produced 232 results in PubMed which increase year by year, so the attention of the scientific community is slowly attracted by this almost unexplored association. To date, there is not a specific drug selected for boosting neurogenesis. Previous works focus their attention on the neuroprotective properties of cannabinoids. More in general, the prevention of neurodegenerative
diseases gained a lot of attention from the scientific community, probably due to lack of drugs capable to resolve the consequences of the disease. However, when the damage is already there, in case of a non-predictable trauma or in the neurodegenerative diseases, the need of a solution cannot be ignored. Neurogenesis is a process not so deeply investigated, indeed to our knowledge the association between cannabinoids and neurogenesis was not reviewed before. The aim of this review is to focus the attention on the phyto- and synthetic cannabinoids effects on neurogenesis, and with the aid of in vitro and in vivo studies we can explore their beneficial effects in a process not so highly represented in literature, but very important for therapeutic point of view.