Screening for cerebroprotective agents using an in vivo model of cerebral reversible depolarization in awake rats.
The need to screen cerebroprotective compounds without anesthetic interference prompted the development of a model using hypoxic rats. In this model two outcome measures were used: (1) the time to reach isoelectric electroencephalogram (iEEG), caused by nitrogen gas inhalation in the test chamber, and (2) the time for behavioral recovery measuring the latency of restoration of the head-withdrawal reflex upon vibrissae stimulation. We report here data of blood chemistry, cerebral tissue oxygen measurements, a definition of a proposed scoring system, and the pharmacological results of RGH-2202. The findings with RGH-2202 are used here to show the utility of the screening method. Events during hypoxia: Arterial and venous pO(2), pCO(2), and pH, and brain tissue pO(2)significantly declined. Significant correlations were established among the pO(2)of cerebral tissue, blood, and the test chamber. RGH-2202 significantly and dose-dependently shortened the iEEG time; the compound's Effective Dose(30)was 227.8 mg kg(-1). Events during recovery: Immediately after the iEEG, when the atmosphere in the chamber was replaced with room air, the arterial, venous and brain tissue pO(2)increased above the control level and subsequently recovered to baseline levels. Behavioral recovery occurred before blood chemistry was otherwise normalized. RGH-2202 significantly and dose-dependently shortened the recovery time; the Effective Dose(30)was 8.71 mg kg(-1). The available data define and support the physiological basis of this practicable rat-screening model.
Bodo
M
M
Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. Michael.Bodo@NA.AMEDD.ARMY.MIL
Perjes
G
G
Kalman
E
E
Bacskai
E
E
Berko
K
K
Sarkadi
A
A
Nagy
I
I
Keim
K L
KL
Matysik
F M
FM
Csomor
K
K
McCarron
R
R
Zagvazdin
Y
Y
Rosenthal
M
M
Morrissette
C
C
Herendy
E
E
Szporny
L
L
Nagy
Z
Z
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation* / Q000379:methods*; D004569:Electroencephalography / Q000187:drug effects / Q000295:instrumentation / Q000379:methods; D002534:Hypoxia, Brain / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D018696:Neuroprotective Agents; D013973:Thyrotropin-Releasing Hormone; C055448:posatirelin