Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition

Govindaiah Vinukonda, Anna Csiszar, Furong Hu, Krishna Dummula, Nishi Kant Pandey, Muhammad T. Zia, Nicholas R. Ferreri, Zoltan Ungvari, Edmund F. LaGamma, Praveen Ballabh

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2264-2280
Number of pages17
JournalBrain
Volume133
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Cyclooxygenase 2
Prostaglandins
Tumor Necrosis Factor-alpha
Hemorrhage
Rabbits
Gliosis
Cyclooxygenase 2 Inhibitors
Tumor Necrosis Factor Receptors
Neuroprotection
Interleukin-1
Dinoprostone
Cytokines
Cyclooxygenase 1
Brain
Cerebral Palsy
Prosencephalon
Premature Infants
Cesarean Section
Glycerol
Cell Death

Keywords

  • Celecoxib
  • Cyclooxygenase-2
  • Germinal matrix haemorrhage
  • Intraventricular haemorrhage
  • Premature rabbit pups
  • Prostanoid receptor
  • Tumour necrosis factor-alpha

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition. / Vinukonda, Govindaiah; Csiszar, Anna; Hu, Furong; Dummula, Krishna; Pandey, Nishi Kant; Zia, Muhammad T.; Ferreri, Nicholas R.; Ungvari, Zoltan; LaGamma, Edmund F.; Ballabh, Praveen.

In: Brain, Vol. 133, No. 8, 08.2010, p. 2264-2280.

Research output: Contribution to journalArticle

Vinukonda, G, Csiszar, A, Hu, F, Dummula, K, Pandey, NK, Zia, MT, Ferreri, NR, Ungvari, Z, LaGamma, EF & Ballabh, P 2010, 'Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition', Brain, vol. 133, no. 8, pp. 2264-2280. https://doi.org/10.1093/brain/awq107
Vinukonda, Govindaiah ; Csiszar, Anna ; Hu, Furong ; Dummula, Krishna ; Pandey, Nishi Kant ; Zia, Muhammad T. ; Ferreri, Nicholas R. ; Ungvari, Zoltan ; LaGamma, Edmund F. ; Ballabh, Praveen. / Neuroprotection in a rabbit model of intraventricular haemorrhage by cyclooxygenase-2, prostanoid receptor-1 or tumour necrosis factor-alpha inhibition. In: Brain. 2010 ; Vol. 133, No. 8. pp. 2264-2280.
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AU - Vinukonda, Govindaiah

AU - Csiszar, Anna

AU - Hu, Furong

AU - Dummula, Krishna

AU - Pandey, Nishi Kant

AU - Zia, Muhammad T.

AU - Ferreri, Nicholas R.

AU - Ungvari, Zoltan

AU - LaGamma, Edmund F.

AU - Ballabh, Praveen

PY - 2010/8

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N2 - 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.

AB - 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.

KW - Celecoxib

KW - Cyclooxygenase-2

KW - Germinal matrix haemorrhage

KW - Intraventricular haemorrhage

KW - Premature rabbit pups

KW - Prostanoid receptor

KW - Tumour necrosis factor-alpha

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