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Updated: Sep 28, 2026
Quantification of Neurovascular Protection Following Repetitive Hypoxic Preconditioning and Transient Middle Cerebral Artery Occlusion in Mice
Published on: May 4, 2015
PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after hypoxia/ischemia
Amanda L Jagolino1, William M Armstead
1Department of Anesthesia, University of Pennsylvania, Philadelphia 19104, USA.
Abstract:
This study characterized the contributions of protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of hypercapnic pial artery dilation (PAD) after hypoxia/ischemia (H/I) in piglets equipped with a closed cranial window. NOC/oFQ (10(-10) M cerebrospinal fluid H/I concentration) impaired hypercapnic PAD (21 +/- 2% vs. 13 +/- 1%). Coadministration of either of the PTK inhibitors genistein or tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10(-10) M) partially prevented the inhibition of hypercapnic PAD compared with that observed in their absence (21 +/- 2% vs. 17 +/- 1% for genistein). After exposure to H/I, PAD in response to hypercapnia was impaired, but pretreatment with either genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such impairment (17 +/- 1% vs. 4 +/- 1% vs. 9 +/- 1% for sham control, H/I, and H/I + genistein pretreatment, respectively). These data show that PTK and MAPK activation contribute to NOC/oFQ-induced impairment of hypercapnic PAD. These data suggest that activation of PTK and MAPK is also involved in the mechanism by which NOC/oFQ impairs hypercapnic PAD after H/I.
Insights
Protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) pathways contribute to nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of cerebral artery dilation following hypoxia/ischemia (H/I). Inhibiting these kinases partially prevented NOC/oFQ effects.
Area of Science:
- Neuroscience
- Cerebrovascular Physiology
- Molecular Signaling
Background:
- Hypoxia/ischemia (H/I) impairs cerebral artery dilation, a critical factor in brain recovery.
- Nociceptin/orphanin FQ (NOC/oFQ) is implicated in cerebrovascular regulation, but its role post-H/I is unclear.
- Protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) pathways are known signaling molecules in cellular responses.
Purpose of the Study:
- To investigate the involvement of PTK and MAPK in NOC/oFQ-mediated impairment of hypercapnic pial artery dilation (PAD) after H/I.
- To determine if inhibiting PTK or MAPK can mitigate NOC/oFQ-induced cerebrovascular dysfunction post-H/I.
Main Methods:
- Utilized a closed cranial window model in piglets to assess hypercapnic PAD.
- Administered NOC/oFQ and specific PTK (genistein, tyrphostin A23) or MAPK (U-0126, PD-98059) inhibitors.
- Evaluated changes in PAD before and after H/I exposure.
Main Results:
- NOC/oFQ significantly impaired hypercapnic PAD following H/I.
- Coadministration of NOC/oFQ with PTK or MAPK inhibitors partially prevented this impairment.
- Pretreatment with PTK or MAPK inhibitors alone also partially protected against H/I-induced PAD impairment.
Conclusions:
- PTK and MAPK activation are key contributors to NOC/oFQ-induced impairment of hypercapnic PAD after H/I.
- Targeting PTK and MAPK pathways may offer a therapeutic strategy to restore cerebrovascular function post-H/I.
