Protease-activated receptor 1 and 4 signal inhibition reduces preterm neonatal hemorrhagic brain injury.
OBJECTIVE
This study examines the role of thrombin's protease-activated receptor (PAR)-1, PAR-4 in mediating cyclooxygenase-2 and mammalian target of rapamycin after germinal matrix hemorrhage.


METHODS
Germinal matrix hemorrhage was induced by intraparenchymal infusion of bacterial collagenase into the right ganglionic eminence of P7 rat pups. Animals were treated with PAR-1, PAR-4, cyclooxygenase-2, or mammalian target of rapamycin inhibitors by 1 hour, and ≤5 days.


RESULTS
We found increased thrombin activity 6 to 24 hours after germinal matrix hemorrhage, and PAR-1, PAR-4, inhibition normalized cyclooxygenase-2, and mammalian target of rapamycin by 72 hours. Early treatment with NS398 or rapamycin substantially improved long-term outcomes in juvenile animals.


CONCLUSIONS
Suppressing early PAR signal transduction, and postnatal NS398 or rapamycin treatment, may help reduce germinal matrix hemorrhage severity in susceptible preterm infants.
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Tim
T
Lekic
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Damon
D
Klebe
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Devin W
DW
McBride
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Anatol
A
Manaenko
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
William B
WB
Rolland
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Jerry J
JJ
Flores
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Orhan
O
Altay
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
Jiping
J
Tang
From the Departments of Physiology and Pharmacology (T.L., D.K., D.W.M., A.M., W.B.R., J.J.F., O.A., J.T., J.H.Z.), Neurology (T.L.), and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA. johnzhang3910@yahoo.com.
John H
JH
Zhang
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D051381:Rats; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D009578:Nitrobenzenes; D018179:Receptors, Thrombin; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C112908:protease-activated receptor 4; D020123:Sirolimus; D010975:Platelet Aggregation Inhibitors
hydrocephalus; stroke