vasoactive-intestinal-peptide and Cerebral-Palsy

Excitotoxicity is a key molecular mechanism of perinatal brain damage and is associated with cerebral palsy and long term cognitive deficits. VIP induces a potent neuroprotection against perinatal excitotoxic white matter damage. VIP does not prevent the initial appearance of white matter lesion but promotes a secondary repair with axonal regrowth. This plasticity mechanism involves an atypical VPAC2 receptor and BDNF production. Stable VIP agonists mimic VIP effects when given systemically and exhibit a large therapeutic window. Unraveling cellular and molecular targets of VIP effects against perinatal white matter lesions could provide a more general rationale to understand the neuroprotection of the developing white matter against excitotoxic insults.

Topics: Animals; Brain; Cerebral Palsy; Humans; Neuronal Plasticity; Neuroprotective Agents; Receptors, Vasoactive Intestinal Peptide, Type II; Signal Transduction; Vasoactive Intestinal Peptide

To estimate the associations between polymorphisms in neuronal homeostasis, neuroprotection, and oxidative stress candidate genes and neurodevelopmental disability.. This was a nested case-control analysis of a randomized trial of magnesium sulfate administered to women at imminent risk for early (before 32 weeks) preterm birth for the prevention of death or cerebral palsy in their offspring. We evaluated 21 single-nucleotide polymorphisms (SNPs) in 17 genes associated with neuronal homeostasis, neuroprotection, or oxidative stress in umbilical cord blood. Cases included infant deaths (n=43) and children with cerebral palsy (n=24), mental delay (Bayley Mental Developmental Index less than 70; n=109), or psychomotor delay (Bayley Psychomotor Developmental Index less than 70; n=91) diagnosed. Controls were race-matched and sex-matched children with normal neurodevelopment. Associations between each SNP and each outcome were assessed in logistic regression models assuming an additive genetic pattern, conditional on maternal race and infant sex, and adjusting for study drug assignment, gestational age at birth, and maternal education.. The odds of cerebral palsy were increased more than 2.5 times for each copy of the minor allele of vasoactive intestinal polypeptipe (VIP, rs17083008) (adjusted odds ratio 2.67, 95% confidence interval 1.09-6.55, P=.03) and 4.5 times for each copy of the minor allele of N-methyl-D-aspartate receptor subunit 3A (GRIN3A, rs3739722) (adjusted odds ratio 4.67, 95% CI 1.36-16.01, P=.01). The association between the advanced glycosylation end product-specific receptor (AGER, rs3134945) SNP and mental delay was modulated by study drug allocation (P=.02).. Vasoactive intestinal polypeptipe and GRIN3A SNPs may be associated with cerebral palsy at age 2 in children born preterm.

Topics: Case-Control Studies; Cerebral Palsy; Child, Preschool; Developmental Disabilities; Female; Genetic Markers; Homeostasis; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intellectual Disability; Logistic Models; Male; Oxidative Stress; Polymorphism, Single Nucleotide; Psychological Tests; Psychomotor Disorders; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Receptors, N-Methyl-D-Aspartate; Vasoactive Intestinal Peptide

The glutamatergic agent ibotenate induces cortical plate and white matter lesions in the newborn mouse, mimicking brain lesions of the human neonate. In this model, co-treatment with ibotenate and a vasoactive intestinal peptide antagonist (VA) aggravates the excitotoxic lesions, suggesting a protective role of endogenous VIP. On the other hand, prenatal injection of VA is followed by a dramatic depletion of astrocytes in the neocortex. Since astrocytes produce numerous neuronotrophic agents, we studied the consequences of a decreased astrocytic density by prenatal VIP blockade on the excitotoxic brain lesions in newborn mice. Pregnant females were pre-treated with VA during the last 2 days of gestation and ibotenate was intracerebrally injected on postnatal day (P) 2 or P5. When compared to controls, pups pre-treated with VA and injected with ibotenate at P2 displayed a significant reduction of the white matter lesion size while cortical plate lesion was not affected. This protective effect disappeared when ibotenate was injected at P5. White matter protection by VA pre-treatment did not seem to be linked to the decreased astrocytic density since, i) this astrocytic paucity concerns only superficial cortical layers and does not affect white matter, ii) protective effects are only observed at P2 while astrocytic density reduction is observed at P2 and P5. This white matter protection could be secondary to an up-regulation of VIP receptors: an increased density of VIP receptors, which was described in other developmental models following VA treatment, could increase the efficacy of the endogenous VIP after an excitotoxic insult.

Topics: Animals; Animals, Newborn; Cerebral Palsy; Disease Models, Animal; Drug Evaluation, Preclinical; Embryonic and Fetal Development; Excitatory Amino Acids; Female; Glutamic Acid; Humans; Ibotenic Acid; Infant, Newborn; Leukomalacia, Periventricular; Mice; Mice, Inbred Strains; Neuroprotective Agents; Pregnancy; Vasoactive Intestinal Peptide