Abstract
Basal ganglia injury at term remains a major cause of disability, such as cerebral palsy. In this study we tested the hypotheses that blockade of astrocytic connexin hemichannels with a mimetic peptide would improve survival of striatal phenotypic neurons after global cerebral ischaemia in term-equivalent fetal sheep, and that neuronal survival would be associated with electrophysiological recovery. Fetal sheep (0.85 gestation) were randomly assigned to receive a short or long (1 or 25 h) intracerebroventricular infusion of a mimetic peptide or vehicle, starting 90 minutes after 30 minutes of cerebral ischaemia. Sheep were killed 7 days after ischaemia. Cerebral ischaemia was associated with reduced numbers of calbindin-28k, calretinin, parvalbumin and GAD positive striatal neurons (P < 0.05 ischaemia + vehicle, n = 6 vs. sham ischaemia, n = 6) but not ChAT or nNOS positive neurons. Short infusion of peptide (n = 6) did not significantly improve survival of any striatal phenotype. Long infusion of peptide (n = 6) was associated with increased survival of calbindin-28k, calretinin, parvalbumin and GAD positive neurons (P < 0.05 vs. ischaemia + vehicle). Neurophysiological recovery was associated with improved survival of calbindin-28k, calretinin and parvalbumin positive striatal neurons (P < 0.05 for all). In conclusion, connexin hemichannel blockade after cerebral ischaemia in term-equivalent fetal sheep improves survival of striatal GABA-ergic neurons.
Highlights
Basal ganglia injury after hypoxia ischaemia (HI) at term remains a major contributor to poor neurodevelopmental outcomes such as cerebral palsy, learning disability and epilepsy[1, 2]
We tested the effect of Cx43 hemichannel blockade on the striatum, a major nucleus within the basal ganglia that is highly susceptible to cerebral ischaemia and where neuronal phenotypes have been well-defined[9, 14]
This study demonstrates that Cx43 hemichannel blockade, starting 90 minutes after global cerebral ischaemia and continued for 24 hours, significantly improved survival of striatal GABA-ergic neurons in term equivalent fetal sheep
Summary
Basal ganglia injury after hypoxia ischaemia (HI) at term remains a major contributor to poor neurodevelopmental outcomes such as cerebral palsy, learning disability and epilepsy[1, 2]. Post-insult blockade of Cx43 hemichannels using a mimetic peptide (Peptide 513), targeting the extracellular loop of Cx43 was associated with improved recovery of EEG power, reduced electrographic seizures and improved survival of oligodendrocytes after global cerebral ischaemia, but only an intermediate improvement in survival of cortical neurons[10, 11]. We tested the secondary hypothesis that improved survival of GABA-ergic striatal neurons would be associated with reduced seizure burden, faster rate of return to sleep state cycling and recovery of EEG activity At this gestational age, brain maturation is equivalent to the human infant at term[15, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
