UFMG Research Shows How Cannabidiol Can Act to Reduce Seizures

Isolated from marijuana (Cannabis sativa), cannabidiol (CBD) does not have the hallucinogenic effects of the plant caused by tetrahydrocannabinol, THC. Currently, its efficacy is recognized in the treatment of certain types of epilepsy, especially in reducing the frequency of so-called refractory epileptic syndromes that resist conventional medications. However, little is still known about how cannabidiol acts in the body.

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A study developed at the Neuropharmacology Laboratory of the Department of Pharmacology at UFMG made an important step towards this knowledge. The article Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway, published in the journal Neuropharmacology, showed – in an animal model – that its anticonvulsant and neuroprotective effect is mediated by phosphatidylinositol 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) proteins, a “signaling pathway,” that is, a kind of communication channel through which cannabidiol “commands” the actions of cells. Normally, this pathway is related to growth, proliferation, protein synthesis, survival, and development of cells.

The research was coordinated by Professor Antônio Carlos Pinheiro de Oliveira from the Department of Pharmacology at ICB and developed together with pharmacist Isabel Vieira de Assis Lima, PhD in Biological Sciences, and collaborators. According to the researchers, understanding the mechanism of action of cannabidiol in the body is essential to enable the optimization of its use and the development of medications that may have similar effects.

Inflammation Caused by Seizure Episodes in the Brain Can Be Alleviated

In the study conducted at UFMG, experiments were developed in living organisms (in vivo) and in controlled environments (in vitro). One of the study's conclusions is that cannabidiol reduces the activation of so-called glial cells, present in the brain and that contribute to the functioning of neurons. These cells are activated in response to seizure episodes, contributing to inflammation and brain injury.

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It was already known that the PI3K/mTOR signaling pathway was associated with other processes in the body, both physiological (normal) and pathological (in diseases). “The activation of PI3K and mTOR by cannabidiol can prevent excessive neuronal activity and prevent severe seizures and neuronal damage,” says Antônio Carlos Pinheiro. It is as if cannabidiol (CBD), he compares, performs a role similar to that of a light switch, which turns the process on and off through a series of complex molecular mechanisms.

The study also suggests that when the activation of these cells is reduced, the inflammation caused by seizure episodes in the brain can also be alleviated. Through genetic and pharmacological tools, the research group discovered that inhibiting the action of the two molecules (mTOR and PI3K) can lead to the loss of the anticonvulsant property of cannabidiol.

One fact observed in the study caught the scientists' attention. Contrary to expectations, when the PI3K-mTOR pathway was inhibited, the anticonvulsant power of valproic acid – a conventional medication used in the treatment of epilepsy – was preserved. “This reinforces our understanding that the mechanism of action of cannabidiol is dependent on this signaling pathway,” concludes Antônio Oliveira.

Epilepsy and Background

In the recently published article, the authors define epilepsy as a neurological disorder characterized by recurrent seizures and the neurobiological, cognitive, and social consequences associated with this condition. “Seizures occur recurrently and spontaneously and are characterized by a hypersynchronized discharge of populations of neurons in the central nervous system (CNS) due to increased excitability,” they explain. They add that temporal lobe epilepsy (TLE) is the most common type in the adult population, and its patients may suffer from focal or secondarily generalized seizures. According to the researchers, there are some compounds available for the treatment of this condition, but they may not be effective in 30% to 50% of cases, hence the need for new pharmacological therapies.

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The main compounds of marijuana, THC and CBD, were isolated by Professor Raphael Mechoulan from the Hebrew University of Jerusalem back in the 1960s. This achievement enabled the development of pharmacological research on many cannabinoids, including regarding their pharmacological mechanism of action and clinical effects. However, prohibitionist policies delayed the development of cannabis-based medications. CBD was only removed from the list of prohibited substances in Brazil five years ago, and only in May 2017 did Anvisa include Cannabis sativa in the list of medicinal plants of medical interest.

Source: UFMG