The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia.
OBJECTIVE
The endocannabinoid system has been involved in the modulation of neural stem cells proliferation, survival and differentiation as well as in the generation of new oligodendrocyte progenitors in the postnatal brain. The present work aims to test the effect of the synthetic Type 1 and Type 2 cannabinoid receptor agonist WIN55212-2 on these processes in the context of neonatal rat brain hypoxia-ischemia (HI).


METHODS
P7 Wistar rats were subjected to HI and treated either with WIN55212-2 (1 mg/kg) or vehicle twice daily for 7 days after HI and euthanized at 1, 2, 7, 14, or 28 days to explore white matter injury progression and the neurogenic response in the subventricular zone after HI.


RESULTS
Our findings reveal that WIN55212-2 promotes remyelination of the injured external capsule, increasing the number of NG2+ early oligodendrocyte progenitors 7 days after HI in this area and the number of APC+ mature oligodendrocytes in the injured striatum 14 and 28 days after HI. WIN55212-2 also increases cell proliferation and protein expression of the neuroblast marker doublecortin in the subventricular zone 7 days after neonatal HI as well as the number of newly generated neuroblasts (5-bromodeoxyuridine+/doublecortin+ cells) in the ipsilateral striatum 14 days after HI.


CONCLUSIONS
Our results suggest that the activation of the endocannabinoid system promotes white and gray matter recovery after neonatal HI injury.
Unidad de Investigación Neurovascular, Madrid, Spain.
David
D
Fernández-López
Jesús M
JM
Pradillo
Isaac
I
García-Yébenes
José A
JA
Martínez-Orgado
María A
MA
Moro
Ignacio
I
Lizasoain
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000963:Antimetabolites; D048588:Benzoxazines / Q000627:therapeutic use*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001973:Bromodeoxyuridine; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D000089662:Doublecortin Protein; D005260:Female; D005455:Fluorescent Antibody Technique; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D009025:Morpholines / Q000627:therapeutic use*; D009281:Naphthalenes / Q000627:therapeutic use*; D009416:Nerve Regeneration / Q000187:drug effects*; D009836:Oligodendroglia / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000963:Antimetabolites; D048588:Benzoxazines; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D001973:Bromodeoxyuridine