Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain.
Excitotoxic damage may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected at birth, the glutamatergic analog ibotenate induces mouse brain lesions that strikingly mimic human microgyria. When ibotenate is injected at postnatal day 5, it produces transcortical necrosis and white matter cysts that mimic human perinatal hypoxic-like lesions. Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective properties that influence mitosis and neuronal survival in culture. The goal of this study was to assess the protective role of VIP against excitotoxic lesions induced by ibotenate in developing mouse brain. VIP cotreatment reduced ibotenate-induced microgyric-like cortical lesions and white matter cysts by up to 77 and 85%, respectively. VIP protective effects were reproduced by a peptide derived from activity-dependent neurotrophic factor (ADNF), a trophic factor released by VIP-stimulated astrocytes, and by stearyl norleucine VIP, a specific VIP agonist that does not activate adenylate cyclase. Neither forskolin, an adenylate cyclase activator, nor pituitary adenylate cyclase-activating peptide, provided VIP-like protection. VIP and neurotrophic analogs, acting through a cAMP-independent mechanism and inducing ADNF release, could represent new avenues in the understanding and prevention of human cerebral palsy.
Gressens
P
P
Service de Neuropédiatrie, Hôpital Robert-Debré and Faculté Xavier Bichat, F-75019 Paris, France. pierre.gressens@rdb.ap-hop-paris.fr
Marret
S
S
Hill
J M
JM
Brenneman
D E
DE
Gozes
I
I
Fridkin
M
M
Evrard
P
P
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006651:Histocytochemistry; D007051:Ibotenic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D009479:Neuropeptides / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides; D010446:Peptide Fragments / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015398:Signal Transduction / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C410622:activity-dependent neurotrophic factor; C086770:stearyl-norleucine(17)-vasoactive intestinal peptide; D005576:Colforsin; D007051:Ibotenic Acid; D014660:Vasoactive Intestinal Peptide