Cannabidiol for the Treatment of Neonatal Hypoxic-Ischemic Brain Injury

Abstract

Each year, more than two million babies die or evolve to permanent invalidating sequelae worldwide because of Hypoxic-Ischemic Brain Injury (HIBI). There is no current treatment for that condition except for therapeutic hypothermia, which benefits only a select group of newborns. Preclinical studies offer solid evidence of the neuroprotective effects of Cannabidiol (CBD) when administered after diffuse or focal HI insults to newborn pigs and rodents. Such effects are observable in the short and long term as demonstrated by functional, neuroimaging, histologic and biochemical studies, and are related to the modulation of excitotoxicity, inflammation and oxidative stress—the major components of HIBI pathophysiology. CBD protects neuronal and glial cells, with a remarkable effect on preserving normal myelinogenesis. From a translational point of view CBD is a valuable tool for HIBI management since it is safe and effective. It is administered by the parenteral route a posteriori with a broad therapeutic time window. Those findings consolidate CBD as a promising treatment for neonatal HIBI, which is to be demonstrated in clinical trials currently in progress.

Can Old Animals Reveal New Targets? The Aging and Degenerating Brain as a New Precision Medicine Opportunity for Epilepsy

“…Studies of naturally aged rodents and genetic SAM models demonstrate that there is an accumulation of oxidation products in the brain over time ( 78 ). Oxidative stress is the result of the aggregation of ROS ( 87 , 88 ). Several factors are involved in ROS accumulation ( 78 ).…”

“…Several factors are involved in ROS accumulation ( 78 ). However, a drastic reduction in the levels of antioxidant enzymes, such as superoxide dismutase, and increased inflammation particularly impact epilepsy in the aged brain ( 87 , 88 ).…”

“…Excitotoxicity describes the toxic actions of excitatory neurotransmitters, mainly glutamate, where exacerbated or prolonged activation of glutamate receptors initiates a cascade of neurotoxicity that ultimately leads to loss of neuronal function and cell death ( 88 , 93 ) ( Figure 1 ). Both inflammation and oxidative stress can induce massive glutamate release.…”

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

“…It is a 21-carbon terpenophenolic compound which is formed following decarboxylation from a cannabidiolic acid precursor, although it can also be produced synthetically. It has a complex pharmacological profile, acting not only on endocannabinoid receptors, CB1 and CB2, but also on G protein-coupled receptors, ion channel, and nuclear receptors [63,64]. While some of the neuroprotective effects of cannabidiol are mediated through CB1 and CB2, it is also partly due to activation of 5-hydroxytryptamine-1A, adenosine, and peroxisome proliferator-activated receptor-gamma (PPARγ) receptors [65][66][67][68].…”

Genetic Inhibition of Plppr5 Aggravates Hypoxic-Ischemie-Induced Cortical Damage and Excitotoxic Phenotype

“…The incidence of HIBD in live births is about 3‰∼6‰, of which about 18% die in the neonatal period, and about 25% of surviving children also have permanent neurological damage ( Horn et al, 2013 ). Every year, more than 2 million babies die or develop permanent sequelae due to HIBD in the world ( Martínez-Orgado et al, 2020 ). A report by The Lancet showed that about 75% of children with HIBD had seizures, and some children developed epilepsy ( Gluckman et al, 2005 ).…”