Neonatal stroke is a prevalent pathology, affecting approximately 1 in 2000 newborns, so that within the neonatal population the incidence of stroke is even more frequent than in adulthood (Dunbar and Kirton, 2019). In most cases the cause is unknown (Dunbar and Kirton, 2019). Very often newborn with stroke do not show any symptoms, or they consists mostly in focal seizures that are usually subtle (Armstrong-Wells and Ferriero, 2014; Dunbar and Kirton, 2019). This implies that more than in half of cases the diagnosis is late (Armstrong-Wells and Ferriero, 2014; Dunbar and Kirton, 2019). Thus, neonatal stroke represents a significant cause of mortality and morbidity in neonates, contributing to the development of neurosensory impairment encompassed within the spectrum of Cerebral Palsy, the most frequent permanent disorder of movement and postures in childhood, often complicated with epilepsia and cognitive impairment (Armstrong-Wells and Ferriero, 2014; Dunbar and Kirton, 2019). In addition, late diagnosis requires that therapeutic strategies must always be effective a posteriori; however, at present, there is a lack of effective treatments to mitigate these consequences (Dunbar and Kirton, 2019). This is primarily due to two major challenges: the intricate nature of its pathophysiology, characterized by the interplay and mutual potentiation of neuroinflammation, excitotoxicity, and oxidative stress (Dunbar and Kirton, 2019). Additionally, the subtle presentation of symptoms in neonates often results in a delayed diagnosis, with approximately 50% of cases being identified months or even years after the initial event (Dunbar and Kirton, 2019). Consequently, the development of multi-target therapies that retain efficacy even when administered post-onset of the disease is imperative, as prevention of neonatal stroke remains elusive.

Cannabidiol has exhibited neuroprotective effects in experimental models of neonatal stroke (Ceprián et al., 2017). One promising derivative of cannabidiol, VCE-004.8, is an aminoquinone compound that exhibits remarkable activity on CB2 and PPARγ receptors, owing to its unique chemical transformation (García-Martín et al., 2019). Furthermore, VCE-004.8 is a first-in-class activator of the protein phosphatase 2A(PP2A)/B55α and as consequence dephosphorylates and inactivates the prolyl hydrolase 2 (PHD2) and stabilizes the expression of the transcription factor hypoxia inducing factor-1a (HIF-1a) (Navarrete et al., 2018, 2022). Notably, VCE-004.8 has also demonstrated neuroprotective effects in animal models of acute brain injury (Lavayen et al., 2023; Navarrete et al., 2022) as well as chronic brain injury (Burgaz et al., 2021; García-Martín et al., 2019; Navarrete et al., 2018, 2020).

The present study aimed to investigate the neuroprotective capacity of VCE-004.8 following neonatal stroke, utilizing a standardized rodent model that replicates the circumstances of neonatal cerebral infarction. Specifically, temporary middle cerebral artery occlusion (MCAO) was induced in 7-day-old rats.