Cannabidiol Reduces Brain Damage and Improves Functional Recovery After Acute Hypoxia-Ischemia in Newborn Pigs

Hector LAFUENTE, Francisco J. ALVAREZ, M. Ruth PAZOS, Antonia ALVAREZ, M. Carmen REY-SANTANO, Victoria MIELGO, Xabier MURGIA-ESTEVE, Enrique HILARIO, and Jose MARTINEZ-ORGADO

Pediatric Research, 2011, 70, 272–277.

ABSTRACT :

Newborn piglets exposed to acute hypoxia-ischemia (HI) received i.v. cannabidiol (HI
CBD) or vehicle (HI
VEH). In HI
VEH, 72 h post-HI brain activity as assessed by amplitudeintegrated EEG (aEEG) had only recovered to 42  9% of baseline, near-infrared spectroscopy (NIRS) parameters remained lower than normal, and neurobehavioral performance was abnormal (27.8  2.3 points, normal 36). In the brain, there were fewer normal and more pyknotic neurons, while astrocytes were less numerous and swollen. Cerebrospinal fluid concentration of neuronal-specific enolase (NSE) and S100
protein and brain tissue percentage of TNF(
) cells were all higher. In contrast, in HI
CBD, aEEG had recovered to 86  5%, NIRS parameters increased, and the neurobehavioral score normalized (34.3  1.4 points). HI induced histological changes, and NSE and S100
concentration and TNF(
) cell increases were suppressed by CBD. In conclusion, post-HI administration of CBD protects neurons and astrocytes, leading to histological, functional, biochemical, and neurobehavioral improvements.

 

Cannabinoids (CBs) have emerged as valuable tools for reducing brain damage after hypoxia-ischemia (HI) in newborns (1). Several effects of CBs such as their anti-inflammatory and anti-oxidant effects, their vasoactive effects, the reduction of Ca2
influx and of glutamate release, and the modulation of nuclear factor (NF)-B activity account for their observed neuroprotective action (1). Usually, CB1 agonists have been considered the best neuroprotective CBs for both the mature (1) and immature (2) brain. Nevertheless, some concern has arisen lately regarding a possible deleterious effect of CB1 overactivation in the immature brain (3). These findings have prompted further investigation of the neuroprotective effect of non-CB1 agonists in the immature brain.

In this regard, our group recently reported that the phytocannabinoid cannabidiol (CBD) successfully reduces immediate brain damage when administered to newborn piglets after HI (4). CBD is the major nonpsychoactive constituent of Cannabis sativa; the lack of psychoactive effects derives from the lack of significant binding to CB1 receptors (5–7). In immature mice brain, it has been shown that some of the neuroprotective effects of CBD are because of interaction with CB2 and adenosine receptors (8). Recently, it has been reported that CBD increases brain levels of adenosine through inhibition of uptake (9). In the newborn piglet model, administration of CBD after HI reduces immediate brain damage by modulating cerebral hemodynamic impairment and brain metabolic derangement and preventing the appearance of brain edema and seizures; these neuroprotective effects are not only free from side effects but also associated with some beneficial cardiac, hemodynamic, and ventilatory effects (4). That study, however, involved only an extremely short follow-up (6 h) and did not include behavioral outcomes. Only studies with follow-ups longer than 24 h post-HI and including neurobehavioral assessment are thought to be valid candidates to be transferred to asphyxiated babies (3,10).

In the present work, we studied the neurobehavioral impairment associated with the derangement of brain activity and metabolism induced by HI in piglets, investigating whether such damage was reduced by CBD administration. Furthermore, in this occasion, we studied HI piglets for longer, up to 72 h post HI insult. This period is commonly selected in this model (10) because biochemical, neuropathological, and neurobehavioral consequences of HI are well established over that interval of time, so the neuroprotective effect of a given strategy can be properly assessed (11,12). In addition, we gained some insight into the mechanisms of CBD neuroprotection in HI piglets. Special attention was paid to a possible protective effect not only on neurons but also on astrocytes, because glial cell protection is now considered indispensable to provide sustained and successful neuroprotection (13).

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