Modulation of ageing mice microglia functions during neuroinflammation using synthetic cannabinoids

Ageing is marked by a gradual rise in systemic inflammation, with neuroinflammation being a key feature. Neuroinflammation, which refers to the immune response within the CNS, is primarily mediated by microglia. These resident macrophages in the CNS parenchyma are essential for maintaining homeostasis and initiating immune responses. Their function depends on the timely activation and deactivation of microglia to regulate these processes effectively. Excessive activation of microglia has been shown to disrupt brain functions and promote a proinflammatory response leading to dysfunctional microglia that are unable to carry out immune response due to various reasons, with major implications in neuroinflammation. Therefore, there is a need to monitor and modulate the functionality of microglia to elicit a healthy immune response. The endocannabinoid system is a negative feedback system that is activated to modulate various mechanisms related to inflammation. In our research, we therefore investigated the functionality of microglia in relation to phagocytosis and oxidative stress during neuroinflammation by stimulating the endocannabinoid receptors Cnr1 and Cnr2 with synthetic cannabinoid compounds in ageing mice. Our results show that the expression of the endocannabinoid system (ECS) increases with age. Activation of CB₁ and CB₂ receptors reduces reactive oxygen species (ROS) in both young and aged mice, with the effect being more pronounced effect in younger mice. In aged mice, the upregulation of these receptors indicates persistent inflammation, while microglial phagocytosis is modulated through CB₁ receptors in both age groups.