Role of integrating cannabinoids and the endocannabinoid system in neonatal hypoxic-ischaemic encephalopathy

Abstract

Neonatal hypoxic-ischaemic events, which can result in long-term neurological impairments or even cell death, are among the most significant causes of brain injury during neurodevelopment. The complexity of neonatal hypoxic-ischaemic pathophysiology and cellular pathways make it difficult to treat brain damage; hence, the development of new neuroprotective medicines is of great interest. Recently, numerous neuroprotective medicines have been developed to treat brain injuries and improve long-term outcomes based on comprehensive knowledge of the mechanisms that underlie neuronal plasticity following hypoxic-ischaemic brain injury. In this context, understanding of the medicinal potential of cannabinoids and the endocannabinoid system has recently increased. The endocannabinoid system plays a vital neuromodulatory role in numerous brain regions, ensuring appropriate control of neuronal activity. Its natural neuroprotection against adult brain injury or acute brain injury also clearly demonstrate the role of endocannabinoid signalling in modulating neuronal activity in the adult brain. The goal of this review is to examine how cannabinoid-derived compounds can be used to treat neonatal hypoxic-ischaemic brain injury and to assess the critical function of the endocannabinoid system and its potential for use as a new neuroprotective treatment for neonatal hypoxic-ischaemic brain injury.

Keywords: HIE; brain development; cannabinoids; endocannabinoid system; neuroprotective.

Figure 1

Simplified scheme representing endocannabinoid system-modulated synaptic transmission. The endocannabinoids AEA and 2-AG are not stored in vesicles but instead are synthesized de novo from phospholipid precursors through calcium-dependent mechanisms. N-acylphosphatidylethanolamine (NAPE) is hydrolysed by N-arachidonoyl-phosphatidylethanolamine-specific phospholipase D (NPLD) to yield AEA, and diacylglycerol (DAG) is converted to 2-AG by diacylglycerol lipase (DAGL). Both endogenous ligands traverse the synaptic cleft and activate presynaptic CB1 receptors, thereby regulating ion channels and ultimately suppressing neurotransmitter release. Endocannabinoid signalling is terminated following degradation by hydrolytic enzymes in the presynaptic and postsynaptic compartments. Primarily, AEA is converted to arachidonic acid (AA) and ethanolamine by fatty acid amide hydrolase (FAAH) localized to the postsynaptic cell, whereas 2-AG is hydrolysed presynaptically into AA and glycerol by monacylglycerol lipase (MAGL).

Figure 2

Endocannabinoid system control of neurogenesis and neural cell fate in the immature brain. CB1 receptor expression is present in neural progenitors (NPs) and increases during neuronal proliferation, differentiation and maturation. In contrast, the CB2 receptor is present in NPs and is downregulated upon neuronal proliferation, differentiation and maturation. During neuronal development, CB1 and CB2 receptors control NP proliferation, neuroblast migration and neuron maturation. Under neuroinflammatory conditions, activation of CB1 receptors has been shown to restore adult neurogenesis and decrease the number of injured neurons.