Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition
| Autor: | Govindaiah Vinukonda, Krishna Dummula, Nicholas R. Ferreri, Zoltan Ungvari, Praveen Ballabh, Nishi Kant Pandey, Anna Csiszar, Muhammad T. Zia, Edmund F. LaGamma, Furong Hu |
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| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Necrosis Interleukin-1beta Brain damage Biology Neuroprotection Dinoprostone Cerebral Ventricles chemistry.chemical_compound medicine Animals Receptors Prostaglandin E Gliosis Prostaglandin E2 Myelin Sheath Cell Death Cyclooxygenase 2 Inhibitors Tumor Necrosis Factor-alpha Brain Prostanoid Original Articles Receptors Prostaglandin E EP1 Subtype Cerebral Intraventricular Hemorrhage Disease Models Animal Neuroprotective Agents Animals Newborn chemistry Cyclooxygenase 2 Caspases Anesthesia Cyclooxygenase 1 Tumor necrosis factor alpha Rabbits Neurology (clinical) medicine.symptom Intracranial Hemorrhages medicine.drug |
| Zdroj: | Brain. 133:2264-2280 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awq107 |
| Popis: | Intraventricular haemorrhage is a major complication of prematurity that results in neurological dysfunctions, including cerebral palsy and cognitive deficits. No therapeutic options are currently available to limit the catastrophic brain damage initiated by the development of intraventricular haemorrhage. As intraventricular haemorrhage leads to an inflammatory response, we asked whether cyclooxygenase-2, its derivative prostaglandin E2, prostanoid receptors and pro-inflammatory cytokines were elevated in intraventricular haemorrhage; whether their suppression would confer neuroprotection; and determined how cyclooxygenase-2 and cytokines were mechanistically-linked. To this end, we used our rabbit model of intraventricular haemorrhage where premature pups, delivered by Caesarian section, were treated with intraperitoneal glycerol at 2 h of age to induce haemorrhage. Intraventricular haemorrhage was diagnosed by head ultrasound at 6 h of age. The pups with intraventricular haemorrhage were treated with inhibitors of cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α; and cell-infiltration, cell-death and gliosis were compared between treated-pups and vehicle-treated controls during the first 3 days of life. Neurobehavioural performance, myelination and gliosis were assessed in pups treated with cyclooxygenase-2 inhibitor compared to controls at Day 14. We found that both protein and messenger RNA expression of cyclooxygenase-2, prostaglandin E2, prostanoid receptor-1, tumour necrosis factor-α and interleukin-1β were consistently higher in the forebrain of pups with intraventricular haemorrhage relative to pups without intraventricular haemorrhage. However, cyclooxygenase-1 and prostanoid receptor 2-4 levels were comparable in pups with and without intraventricular haemorrhage. Cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-α inhibition reduced inflammatory cell infiltration, apoptosis, neuronal degeneration and gliosis around the ventricles of pups with intraventricular haemorrhage. Importantly, cyclooxygenase-2 inhibition alleviated neurological impairment, improved myelination and reduced gliosis at 2 weeks of age. Cyclooxygenase-2 or prostanoid receptor-1 inhibition reduced tumour necrosis factor-α level, but not interleukin-1β. Conversely, tumour necrosis factor-α antagonism did not affect cyclooxygenase-2 expression. Hence, prostanoid receptor-1 and tumour necrosis factor-α are downstream to cyclooxygenase-2 in the inflammatory cascade induced by intraventricular haemorrhage, and cyclooxygenase-2-inhibition or suppression of downstream molecules--prostanoid receptor-1 or tumour necrosis factor-α--might be a viable neuroprotective strategy for minimizing brain damage in premature infants with intraventricular haemorrhage. |
| Databáze: | OpenAIRE |
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