Endocannabinoid signaling and the role of FAAH and MAGL on hyperexcitability in neurological conditions

Video transcript 

(light music) [Narrator]

[00:00-00:12]

Well-regulated signaling pathways are essential for healthy brain function.

[00:13-00:32]

Higher-than-normal signaling or neuronal hyperexcitability can be harmful. Hyperexcitability has been observed in many neurological conditions contributing to their symptoms, such as Alzheimer's disease agitation and spasticity associated with multiple sclerosis.

[00:33-00:45]

Endocannabinoids are natural signaling molecules in the body that bind to cannabinoid receptors to help regulate the flow of neuronal information in the brain, spinal cord and peripheral nervous system.

[00:46-01:06]

Much like a traffic officer patrolling busy roadways for safety, endocannabinoids modulate neurotransmission to keep it at healthy levels. As a result, endocannabinoids play a key role in avoiding hyperexcitability and reducing its harmful effects in the brain, spinal cord and peripheral nervous system.

[01:07-01:29]

But the brain can also remove endocannabinoids as part of a homeostatic control mechanism. Fatty acid amide hydrolase, or FAAH, and monoacylglycerol lipase, or MAGL are enzymes found in neurons that break down the two main endocannabinoids: anandamide (AEA) and 2-arachidonylglycerol (2-AG).

[01:30-1:59]

FAAH and MAGL act as regulatory supervisors, maintaining the right balance of endocannabinoids and their control function within the brain. However, in certain neurological conditions where endocannabinoid levels are already low, further removal by FAAH and MAGL can lead to unwanted neuronal hyperexcitability and contribute to dysfunction.

[02:00-02:15]

The signal dysregulation associated with hyperexcitability can occur at one neural roadway or entire brain neighborhoods, leading to more widespread dysfunction depending on the condition and its severity.

[02:16-02:35]

Researchers are investigating ways to increase natural endocannabinoid levels in the brain to re-establish healthy levels of neurotransmission and potentially treat symptoms of certain neurological conditions such as Alzheimer's disease agitation and spasticity associated with multiple sclerosis.

[02:36-03:04]

BMS is exploring the inhibition of FAAH and MAGL enzymes as one such way to raise levels of endocannabinoids within the brain. This mechanism may help improve functional outcomes associated with hyperexcitability across multiple neurological conditions.