Cannabidiol Administration Prevents Hypoxia-Ischemia-Induced Hypomyelination in Newborn Rats.

María Ceprián,Carlos Vargas,Laura García-Toscano,Federica Penna,Izaskun Elezgarai,Svein Achicallende,José Martínez-Orgado,Pedro Grandes,William Hind,M Ruth Pazos,Laura Jiménez-Sánchez

doi:10.3389/fphar.2019.01131

Abstract

Neonatal hypoxia-ischemia (HI) is a risk factor for myelination disturbances, a key factor for cerebral palsy. Cannabidiol (CBD) protects neurons and glial cells after HI insult in newborn animals. We hereby aimed to study CBD’s effects on long-lasting HI-induced myelination deficits in newborn rats. Thus, P7 Wistar rats received s.c. vehicle (HV) or cannabidiol (HC) after HI brain damage (left carotid artery electrocoagulation plus 10% O2 for 112 min). Controls were non-HI pups. At P37, neurobehavioral tests were performed and immunohistochemistry [quantifying mature oligodendrocyte (mOL) populations and myelin basic protein (MBP) density] and electron microscopy (determining axon number, size, and myelin thickness) studies were conducted in cortex (CX) and white matter (WM). Expression of brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) were analyzed by western blot at P14. HI reduced mOL or MBP in CX but not in WM. In both CX and WM, axon density and myelin thickness were reduced. MBP impairment correlated with functional deficits. CBD administration resulted in normal function associated with normal mOL and MBP, as well as normal axon density and myelin thickness in all areas. CBD’s effects were not associated with increased BDNF or GDNF expression. In conclusion, HI injury in newborn rats resulted in long-lasting myelination disturbance, associated with functional impairment. CBD treatment preserved function and myelination, likely as a part of a general neuroprotective effect.

Highlights

Neonatal hypoxia-ischemia (HI) is a major cause of neonatal encephalopathy (Volpe 2012; Lee et al, 2013)
We hereby confirmed that acute HI insult led to the impairment of myelination in rat brains at a developmental stage comparable to that of term human infants
This is noteworthy since most studies on myelination impairment have focused on white matter (WM) injury in models of very preterm or late preterm newborns (Back et al, 2002a; Back et al, 2002b; Segovia et al, 2008; Back 2014; Back and Rosenberg 2014)

Summary

Introduction

Neonatal hypoxia-ischemia (HI) is a major cause of neonatal encephalopathy (Volpe 2012; Lee et al, 2013). In the core of the lesion, axonopathy has been observed to overlap with hypomyelination in microscopic necrosis region (Buser et al, 2012; Back et al, 2002a). This damage in white and grey matter has been correlated with a poorer pathology outcome, such as motor impairment, delay in language, and behavioral problems (de Vries and Jongmans, 2010; Martinez-Biarge et al, 2011)

Objectives

Methods

Conclusion