Cannabidiol alleviates the inflammatory response in rats with traumatic brain injury through the PGE2-EP2-cAMP-PKA signaling pathway

Abstract

Traumatic brain injury (TBI) is a recognized global public health problem. However, there are still limitations in the available therapeutic approaches and a lack of clinically effective drugs. Therefore, an in-depth exploration of the secondary pathological mechanism of TBI and the identification of new effective drugs are urgently needed. Cannabidiol (CBD), a component derived from the cannabis plant, has potential therapeutic effects on neurological diseases and has received increasing attention. However, few reports on CBD intervention in TBI patients exist. Here, we use the Feeney free-fall method to establish a rat TBI model. CBD significantly improves neurological deficit scores, neuronal damage and blood-brain barrier permeability in rats and significantly inhibits the expressions of the brain injury markers S-100β and NSE. Mechanistically, CBD attenuates TBI-induced astrocyte activation, reduces inflammation, and attenuates the expressions of inflammatory prostaglandin system indicators. The use of TG6-10-1 (EP2 inhibitor) and H-89 (PKA inhibitor) indicates that CBD attenuates TBI-induced neurological damage via the PGE2-EP2-cAMP-PKA signaling pathway. Overall, this research provides a novel drug candidate for the treatment of clinical brain trauma.

1. Introduction

Traumatic brain injury (TBI) caused by external mechanical force severely impacts brain function and instigates pathological alterations in neural tissue [1]. Classified as a central nervous system disorder, TBI is characterized by high incidence, disability, and mortality rates, with an estimated 69 million new cases reported globally each year [2], and is a common cause of death among adult males [3].

The pathophysiology of TBI includes the primary destruction of brain tissues and secondary cascading reactions. As primary brain injury stemming from direct mechanical force is typically irreversible, current therapeutic interventions primarily aim to mitigate the severity of subsequent secondary brain injuries. The neuroinflammatory response, a crucial element exacerbating secondary injury, involves the activation of microglia and astrocytes, the release of inflammatory factors, and the infiltration of peripheral immune cells into the brain parenchyma via a compromised blood-brain barrier (BBB) [4]. Astrocytes constitute approximately 30%–40% of the cells in the central nervous system and are integral to the structural and functional integrity of the BBB. These cells also engage in extensive interactions with other central nervous system cells, including neurons. After brain injury, astrocytes become overactivated, leading to the release of toxins that mediate brain edema and inflammatory reactions, further exacerbating brain injury [5]. Consequently, targeting the suppression of excessive inflammation may be a pivotal strategy for alleviating astrocyte hyperactivation.