How uncontrolled inflammation leads to brain cell loss

In a study of inflammation mechanisms in the brain, researchers from the University of Bonn in Germany have identified how, as we get older, a vicious cycle of poorly regulated inflammatory responses leads to the loss of brain cells.

Recently, those researchers conducted a study that investigated the mechanisms that regulate inflammation in the brain, what happens when they stop working properly, and why that may happen.

The cannabinoid receptor type 1 (CB1), they say, plays an important role in processing the "rush" sensation produced by cannabis.

It also appears to be involved in the regulation of inflammatory reactions in the brain.

If CB1 receptors fail to respond, this contributes to the development of chronic inflammation, which can eventually lead to the loss of brain cells. So reports the study paper, now published in the journal Frontiers in Molecular Neuroscience.

'Brake signals' for inflammation

The researchers say that the immune response in the brain is mounted via microglial cells, a type of specialized immune cell found in the central nervous system, which includes the brain and the spinal chord.

Microglia work by responding to bacteria and clearing out malfunctioning nerve cells. At the same time, they send signals to recruit other types of immune cells and trigger inflammation when needed.

However, if unregulated, an inflammatory reaction in the brain can misguidedly attack and damage healthy brain tissue.

"We know that so-called endocannabinoids play an important role in this," explains study co-author Dr. Andras Bilkei-Gorzo. "[Endocannabinoids]," he goes on, "are messenger substances produced by the body that act as a kind of brake signal: [t]hey prevent the inflammatory activity of the glial cells."

These messenger substances act by binding to certain receptors, one of which is CB1. A second one is cannabinoid receptor type 2 (CB2).

Microglial cells have low levels of CB2, and even less, or no, CB1, the researchers explain. Still, these immune cells will react to endocannabinoids despite this lack.

"However, microglial cells have virtually no CB1 and very low level of CB2 receptors. They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals — why this is the case, has been puzzling so far."

Dr. Andras Bilkei-Gorzo

Neurons that 'translate' endocannabinoids

This is precisely the riddle that Dr. Bilkei-Gorzo and colleagues set out to solve in the current study. The investigation began with the observation that there is a certain group of neurons containing a large number of CB1 receptors.

The researchers worked with specially engineered mice, in which the CB1 receptors found in these neurons had been switched off.

Dr. Bilkei-Gorzo says, "The inflammatory activity of the microglial cells was permanently increased in these animals." However, in mice with fully functioning CB1 receptors, inflammation was regulated as usual.

"Based on our results," he says, "we assume that CB1 receptors on neurons control the activity of microglial cells."

This has led the researchers to theorize that microglial cells do not communicate with other nerve cells directly. Instead, the scientists believe, microglial cells release endocannabinoids, and these bind to the CB1 receptors found in nearby neurons.

These neurons might be able to communicate with other nerve cells, and the immune response is thus indirectly regulated.

However, Dr. Bilkei-Gorzo and his team explain that with age, the production of endocannabinoids progressively decreases, leading to the improper regulation of immune responses and potentially to chronic inflammation.

"Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode," says Dr. Bilkei-Gorzo.

"More regulatory neurons die as a result, so the immune response is less regulated and may become free-running," he adds.

Can cannabis prevent brain aging?

The authors warn that, since the results were obtained in mice, they cannot yet be clearly extended to humans, and further research is needed to confirm that the same mechanisms apply.

Nevertheless, they are hopeful that, in the future, understanding these processes will mean that we will be able to develop drugs to act on them as necessary — particularly to prevent chronic inflammation.

Since the receptors activated to regulate inflammation are cannabinoid receptors, the team also suggests that cannabis may be a promising solution.

Tetrahydrocannabinol (THC), which is one of the main active substances in cannabis, is effective in activating CB1 — even when administered in low doses, the authors explain. This may help reduce inflammation and prevent the loss of brain cells.

Research conducted last year by the same scientists — alongside colleagues from other institutions across the world — also suggested that THC is able to restore cognitive function in the brains of aging mice, offering hope that the same may be possible for humans.