Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury

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Abstract

Fluid percussion brain injury elevates the cerebrospinal fluid (CSF) concentration of the opioid nociceptin/orphanin FQ (N/OFQ), which potentiates vasoconstriction to the prostaglandins U 46619, a thromboxane A2 mimic, and prostaglandin (PG)F2a. This study investigated the role of the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) isoforms of mitogen activated protein kinase (MAPK) in potentiated prostaglandin vasoconstriction after brain injury and the relationship of brain injury induced release of N/OFQ to MAPK. Pial artery diameter was measured with a video microscaler by observation through a glass coverslip cranial window placed in the parietal cortex of newborn pigs. Brain injury potentiated U 46619 induced pial artery vasoconstriction but U 0126 and SB 203580 (10 6 and 10 5 M, respectively) (ERK and p38 MAPK inhibitors) blocked the potentiation. In contrast, administration of SP 600125 (10 6 and 10 5 M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI. Co-administration of N/OFQ (10 10 M), the CSF concentration observed after brain injury, with U 46619 or PGF2a under non brain injury conditions potentiated prostaglandin vasoconstriction but U 0126 and SB 203580 blocked such potentiation. Administration of SP 600125 modestly attenuated prostaglandin potentiation by N/OFQ. These data show that activation of ERK and p38 primarily contribute to potentiation of prostaglandin constriction after brain injury. These data suggest that N/OFQ differentially activates ERK, p38, and JNK MAPK to contribute to potentiated prostaglandin vasoconstriction after fluid percussion brain injury.

Introduction

Traumatic brain injury is a leading cause of morbidity and mortality in infants and children (Duhaime et al., 1987, Rodriguez and Brown, 1990). Fluid percussion brain injury is an experimental model for blunt head trauma (Gennarelli, 1994). Although the effects of brain injury have been well documented in adult animal models (McIntosh et al., 1989), less has been reported on the effects of brain injury in the newborn or the mechanisms underlying injury associated changes in cerebral hemodynamics.

Prostaglandins are present in cortical periarachnoid cerebrospinal fluid (CSF) in concentrations that are in the vasoactive range under resting conditions and contribute to the regulation of cerebral hemodynamics in the newborn pig (Leffler et al., 1993). The predominant prostaglandins in the piglet are prostaglandin (PG) E2, PGI2, and thromboxane A2 (TXA2) (Leffler et al., 1993). Prostaglandin concentrations and/or rates of synthesis have been shown to increase after traumatic brain injury in the adult cat and rat and newborn pig (Al-Turki and Armstead, 1998, Ellis et al., 1981, Sohami et al., 1987). Additionally, in human head injury, ventricular CSF arachidonic acid and prostaglandin levels were elevated in brain injured patients (Westcott et al., 1987). The ratio of CSF TXB2 to 6 keto PGF1a, the stable breakdown products of TXA2 and PGI2, respectively, is increased after fluid percussion brain injury in the pig, while the cyclooxygenase inhibitor indomethacin blunted injury induced pial artery vasoconstriction, suggesting that constrictor prostaglandins contribute to reductions in cerebral blood flow following brain injury (Al-Turki and Armstead, 1998). Pial artery vasoconstriction to the TXA2 mimic 9,11 Dideoxy-11α9α-epoxymethanoPGF2a (U 46619), and PGF2a was also observed to be potentiated following fluid percussion brain injury in the piglet (Ford and Armstead, 2004). However, the mechanism which might contribute to altered prostaglandin vascular activity post insult is less well understood.

Similar to prostaglandins, opioids are important in the control of the piglet cerebral circulation during physiologic and pathologic conditions including brain injury (Armstead, 1997). A new member of the opioid family has recently been recognized. Because this opioid like receptor displayed no affinity for known opioid ligands, it remained an “orphan” until two independent groups (Meunier et al., 1995, Reinscheid et al., 1995), identified a 17 amino acid peptide that did not bind to the classic opioid receptors but instead activated the orphan receptor. This peptide was named “orphanin FQ” by Reinscheid et al., 1995 because its sequence begins with phenylalanine (F) and ends with glutamine (Q). The same peptide was called nociceptin by Meunier et al., 1995 because it increased the reactivity to pain in animals in contrast with the analgesic effects of opioid drugs. Nociceptin/orphanin FQ (N/OFQ) concentration is elevated in CSF and contributes to impaired cerebral hemodynamics following fluid percussion brain injury in the piglet (Armstead, 2000, Armstead, 2002). N/OFQ additionally contributes to the potentiation of prostaglandin vasoconstriction after fluid percussion brain injury (Ford and Armstead, 2004). However, the mechanism whereby N/OFQ enhances prostaglandin constriction post insult is unknown.

Activation of protein kinase C (PKC) is thought to contribute to the cerebral vasospasm associated with pathologic conditions such as subarachnoid hemorrhage (Laher and Zhang, 2001). Activation of PKC, in turn, promotes interaction with other more distal signaling pathways, such as protein tyrosine kinase and its substrate, mitogen activated protein kinase (MAPK), also thought to contribute to vasospasm (Laher and Zhang, 2001). MAPK is actually a family of kinases: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) (Laher and Zhang, 2001). Previous studies have indicated that traumatic brain injury induces the expression of neurotrophin related mRNA and receptors (Hicks et al., 1999, Oyesiku et al., 1999), which subsequently triggers downstream MAPK cascades (Otani et al., 2002) through interactions with high affinity tyrosine kinase receptors (Bonni et al., 1999). Interestingly, N/OFQ may activate MAPK (Harrison and Grandy, 2000).

Therefore, the present study investigated the role of ERK, p38, and JNK isoforms of MAPK in potentiated prostaglandin vasoconstriction after fluid percussion brain injury and the relationship of brain injury induced release of N/OFQ to MAPK in such vascular impairment. The study design used an approach in which vascular responses to U 46619 and PGF2a were obtained before and after fluid percussion brain injury in the absence and presence of the ERK MAPK inhibitor [1.4-diamino-2,3-dicyano-1,4-bis (O-aminophenylmercapto)butadiene] (U 0126), the p38 MAPK inhibitor (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole) (SB 203580), and the JNK MAPK inhibitor Anthra[1-9-cd]pyrazol-6(2H)-one (SP 600125). Similarly, responses to these prostaglandins were obtained before and after co-administered N/OFQ before and after the administration of the respective MAPK inhibitors.

Section snippets

Methods

Newborn pigs (1–5 days old, 1.0–1.7 kg) of either sex were used in these experiments. All protocols were approved by the Institutional Animal Care and Use Committee. Animals were sedated with isoflurane (1–2 minimum alveolar concentration). Anesthesia was maintained with a-chloralose (30–50 mg/kg. supplemented with 5 mg/kg/h i.v.). A catheter was inserted into a femoral artery to monitor blood pressure and to sample for blood gas tensions and pH. Drugs to maintain anesthesia were administered

Role of ERK, p38, and JNK MAPK isoform activation and N/OFQ in potentiated pial artery vasoconstriction to prostaglandins after fluid percussion brain injury

Topical U 46619 (1, 10 ng/ml) and PGF2a (10, 100 ng/ml) elicited reproducible pial small artery (120–160 μm) and arteriole (50–70 μm) vasocontriction (data not shown). Prostaglandin pial small artery vasoconstriction was potentiated after fluid percussion brain injury (Fig. 1). However, pretreatment with the ERK and p38 MAPK antagonists U 0126 (10 6 M) and SB 203580 (10 5 M), respectively, completely blocked the potentiation of responses to U 46619 and PGF2a observed after fluid percussion

Discussion

Results of the present study show that vasoconstriction to U 46619 and PGF2a was potentiated after fluid percussion brain injury, consistent with previous observations (Ford and Armstead, 2004). New information in this study shows that pretreatment with either the ERK or p38 MAPK isoform antagonists, U 0126 and SB 203580, respectively (Bolla et al., 2002, Laher and Zhang, 2001), completely blocked brain injury induced potentiation of vasoconstriction. However, pretreatment with the JNK MAPK

Acknowledgments

The author thanks Antonio Pedulla for excellent technical assistance in the performance of the experiments. This research was supported by grants from the National Institutes of Health and the University of Pennsylvania Research Foundation.

References (30)

  • W.M. Armstead

    Role of nociceptin/orphanin FQ in age dependent cerebral hemodynamic effects of brain injury

    J. Neurotrauma

    (2000)
  • W.M. Armstead

    Age dependent NOC/oFQ contribution to impaired hypotensive cerebral hemodynamics following brain injury

    J. Neurotrauma

    (2002)
  • W.M. Armstead et al.

    Influence of endothelin on piglet cerebral microcirculation

    Am. J. Physiol.

    (1989)
  • D. Baranov et al.

    Prostaglandins contribute to impaired angiotensin II induced cerebral vasodilation after brain injury

    J. Neurotrauma

    (2002)
  • B.L. Bennett et al.

    SP 600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase

    Proc. Natl. Acad. Sci.

    (2001)
  • Cited by (0)

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