Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain
P Gressens1, S Marret, J M Hill
1Service de Neuropédiatrie, Hôpital Robert-Debré and Faculté Xavier Bichat, F-75019 Paris, France. pierre.gressens@rdb.ap-hop-paris.fr
Abstract:
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.
Insights
Vasoactive intestinal peptide (VIP) significantly protects developing mouse brains from excitotoxic damage that models cerebral palsy. VIP and its analogs offer potential new strategies for preventing brain lesions in infants.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Excitotoxic brain damage is a key factor in cerebral palsy development.
- Ibotenate, a glutamate analog, induces lesions mimicking human microgyria and perinatal hypoxic injuries in mice.
- Vasoactive intestinal peptide (VIP) exhibits neuroprotective and growth-promoting properties.
Purpose of the Study:
- To investigate the protective effects of VIP against ibotenate-induced excitotoxic brain lesions in developing mice.
- To explore the mechanisms underlying VIP's neuroprotection, including its interaction with activity-dependent neurotrophic factor (ADNF).
Main Methods:
- Developing mice were administered ibotenate to induce excitotoxic lesions.
- Vasoactive intestinal peptide (VIP) was co-administered to assess its protective efficacy.
- Lesion sizes (microgyria-like cortical lesions and white matter cysts) were quantified.
- The effects of VIP analogs and other signaling molecules (forskolin, pituitary adenylate cyclase-activating peptide) were evaluated.
Main Results:
- VIP cotreatment reduced ibotenate-induced microgyric-like cortical lesions by up to 77%.
- VIP significantly decreased white matter cysts by up to 85%.
- Neuroprotective effects were replicated by an ADNF-derived peptide and a specific VIP agonist (stearyl norleucine VIP), independent of adenylate cyclase activation.
Conclusions:
- VIP demonstrates significant neuroprotective effects against excitotoxic brain injury in a developing mouse model of cerebral palsy.
- VIP's protective action appears to be mediated through a cAMP-independent pathway, involving ADNF release.
- VIP and its analogs represent promising therapeutic avenues for preventing cerebral palsy-related brain damage.
