Postischemic Infusion of Apigenin Reduces Seizure Burden in Preterm Fetal Sheep

Author:

Cho Kenta H. T.1,Hounsell Natalya1,McClendon Evelyn2,Riddle Art2,Basappa 3ORCID,Dhillon Simerdeep K.1,Bennet Laura1,Back Stephen24,Sherman Larry S.56ORCID,Gunn Alistair J.1ORCID,Dean Justin M.1ORCID

Affiliation:

1. Department of Physiology, University of Auckland, Auckland 1142, New Zealand

2. Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA

3. Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India

4. Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA

5. Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR 97006, USA

6. Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA

Abstract

Seizures are common in preterm newborns and are associated with poor neurodevelopmental outcomes. Current anticonvulsants have poor efficacy, and many have been associated with upregulation of apoptosis in the developing brain. Apigenin, a natural bioactive flavonoid, is a potent inhibitor of hyaluronidase and reduces seizures in adult animal models. However, its impact on perinatal seizures is unclear. In the present study, we examined the effect of apigenin and S3, a synthetic, selective hyaluronidase inhibitor, on seizures after cerebral ischemia in preterm fetal sheep at 0.7 gestation (98–99 days, term ~147 days). Fetuses received sham ischemia (n = 9) or ischemia induced by bilateral carotid occlusion for 25 min. Immediately after ischemia, fetuses received either a continuous infusion of vehicle (0.036% dimethyl sulfoxide, n = 8) or apigenin (50 µM, n = 6). In a pilot study, we also tested infusion of S3 (2 µM, n = 3). Fetuses were monitored continuously for 72 h after ischemia. Infusion of apigenin or S3 were both associated with reduced numbers of animals with seizures, total seizure time, and mean seizure burden. S3 was also associated with a reduction in the total number of seizures over the 72 h recovery period. In animals that developed seizures, apigenin was associated with earlier cessation of seizures. However, apigenin or S3 treatment did not alter recovery of electroencephalographic power or spectral edge frequency. These data support that targeting brain hyaluronidase activity with apigenin or S3 may be an effective strategy to reduce perinatal seizures following ischemia. Further studies are required to determine their effects on neurohistological outcomes.

Funder

Health Research Council of New Zealand

Cure Kids

Oregon National Primate Research Center

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference67 articles.

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2. Preterm neonatal morbidity and mortality by gestational age: A contemporary cohort;Manuck;Am. J. Obstet. Gynecol.,2016

3. Potential biomarkers for hypoxic-ischemic encephalopathy;Bennet;Semin. Fetal Neonatal Med.,2010

4. Zhou, K.Q., McDouall, A., Drury, P.P., Lear, C.A., Cho, K.H.T., Bennet, L., Gunn, A.J., and Davidson, J.O. (2021). Treating Seizures after Hypoxic-Ischemic Encephalopathy-Current Controversies and Future Directions. Int. J. Mol. Sci., 22.

5. Pathophysiology of hypoxic-ischemic encephalopathy: A review of the past and a view on the future;Greco;Acta Neurol. Belg.,2020

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