Our body’s cannabinoid receptor system may play a part in protecting our nervous system following trauma, Israeli researchers believe.
A team at the Hebrew University of Jerusalem has found that rats and mice subjected to traumatic brain injury (TBI) showed significantly better recovery when treated with cannabinoid compounds, possibly opening the way for clinical trials in the near future.
Cannabinoids are chemical compounds, either derived from cannabis or manufactured, that act on specific cannabinoid receptors in our body’s cells. The most well-known is tetrahydrocannabinol, or THC, marijuana’s main psychoactive compound. The endocannabinoid system, our body’s natural cannabinoid receptors, is found in the brain and most organs of the body, and is believed to be a part of the neuroprotective mechanism in mammals, said Prof. Esther Shohami of the Hebrew University of Jerusalem.
When an external event like stroke or trauma occurs, the body responds by producing these molecules that should protect the brain, Shohami said. In previous studies, the researchers looked at the endocannabinoid 2-AG in mice following a traumatic brain injury. 2-AG is produced by the body naturally, but in relatively low amounts that are not enough to effectively protect the brain.
The researchers noticed that 2-AG levels were significantly higher following trauma, although they weren’t sure why.
“A high level doesn’t mean anything, what matters is what it’s there for,” Shohami said.
They administered additional plant-derived 2-AG to mice following a brain injury, and found that the compound helped the mice recover.
“It is administered by the brain but it’s not enough to protect the brain, so we had to augment,” Shohami said. “The brain creates protection; we wanted to mimic what the brain does, and we wanted to do it better.”
The mice only received a single dose, but showed positive effects up to three months after the injury. 2-AG’s main effect is as an anti-inflammatory compound, Shohami said.
“The outcome of trauma was better, the motor function, the cognitive function,” Shohami said. “All the parameters we looked at as part of the damage were affected by the 2-AG, and were better than the untreated mice.”
The problem was that both cannabinoid receptors type 1 and 2, or CB1 and CB2, were involved in the response. CB1 is responsible for the psychoactive effects of cannabinoids, and is less stable, so it could not be used as a drug. CB2 is not involved in the psychoactive effects of cannabinoids.
“If you can distinguish between the two receptors you can make this drug more attractive for pharma, for doctors to prescribe, because the concern about side effects would be significantly reduced,” Shohami said.
Shohami and her team developed synthetic molecules, modeled on 2-AG, that selectively activate the CB2 receptors and do not bind to the psychoactive, CB1 receptors. The researchers looked at the effect of these molecules, called HU-910 and HU-914, on rats following a closed head injury. They studied the effects of the compounds on both the rats’ brains and on the corticospinal tracts, a neural pathway originating in the brain which extends down the spinal cord and is responsible for the body’s motor control. No one had looked at the effects of cannabis on the corticospinal tract before, Shohami said.
The researchers found improved recovery after TBI in the brain and in this tract, and improved motor skills, which is one important parameter of recovery.
There are no drugs approved for treating traumatic brain injury, Shohami said, partly due to failures in developing treatment by the industry in the 1990s and 2000s, which has made drug companies reluctant to endorse new treatments.
“It’s a very complex condition. Treatment has to be very carefully designed both in terms of mechanism and timing. Timing of treatment is very critical and this was the basis of failure for many of the trials,” Shohami said.
The drug would need to be administered as a single dose in a specific therapeutic window within a few hours of the injury.
Not all of the team’s data has been published, but the researchers hope the treatment will advance to clinical trials, and eventually become a prescribed treatment for TBI.
Prof. Raphael Mechoulam, who collaborated on the research, first discovered the structure of THC. Mechoulam also uncovered the endocannabinoid system in the 1990s.Shohami will present her research, titled “The role of CB2 receptors in the recovery of mice after traumatic brain injury,” at the Cann10 International Medical Cannabis Conference, which will be held in Tel Aviv on June 4-6.