PREVENTION OF HYPOXIC BRAIN DAMAGE IN THE NEWBORN (BIRTH ASPHYXIA, ADENOSINE POTENTIATION, NEONATAL ENCEPHALOPATHY, PD 81,273).
Contributors: University of California, Los Angeles.
Published: 1996
Number of pages: 167
Subjects: Health Sciences, Nursing.; Health Sciences, Obstetrics and Gynecology.; Biology, Neuroscience.; Health Sciences, Pharmacology.
Description: Perinatal asphyxia remains an important cause of brain damage. Glutamate activation of N-methyl-D-aspartate receptors (NMDA) is thought to play a key role in triggering the cytotoxic cascade. Stimulation of adenosine A$\sb1$ receptors limits excessive glutamate release and thereby may reduce neuronal damage. PD 81,273 enhances adenosine binding to A$\sb1$ receptors, thus enhancing this neuroprotective pathway.

This study's purpose was to conduct the first stage in-vivo evaluation of a novel agent, the adenosine binding enhancer PD 81,273, as a neuroprotective agent. According to a well-established newborn rat model of hypoxia-ischemia, thirty litters of postnatal day 7-8 day animals were subjected to unilateral carotid artery ligation and exposure to hypoxia (8% oxygen) 3 h. Thirty minutes before the hypoxia, paired littermates received either the test dose of PD 81,273 or an equivalent volume of the test vehicle. One pup from each litter was not subjected to the insult, but set aside as a normal animal control, as well as one whole litter also used as normal control. Seven days later, brain injury protection was assessed by differences in hemispheric weights. Cellular damage was verified by histopathologic analysis in a representative sample.

The initial series of experiments demonstrated that the most biocompatabile solvent for PD 81,273 was 1% DMSO, that in response to the hypoxic-ischemic insult, vulnerability to brain damage was highly correlated to a $>$14.5 gms mean pup weight/litter and PD 81,273 3 mg/kg/10ml i.p. was within the most protective range of the graded-dose curve.

Using these findings for the protocol in the final series of experiments (N = 5 litters, 53 pups), PD 81,273 provided a 52% reduction in brain injury (p = 0.02). The vehicle-control group (n = 15) revealed a 30 $\pm$ 3.9% loss in left hemispheric weight, whereas only a 15 $\pm$ 4% loss was noted in the PD 81,273- treated pups. The normal control group (n = 20) showed a 3 $\pm$ 0.1% loss (cutting error). Light microscopic examinations of cortex and hippocampus verified the hemispheric weight loss was due to cellular loss. These findings indicate that enhancing adenosine binding by PD 81,273 in the perinatal brain can significantly ameliorate brain injury.
Notes: Source: Dissertation Abstracts International, Volume: 57-09, Section: B, page: 5574.

Thesis (PH.D.)--UNIVERSITY OF CALIFORNIA, LOS ANGELES, 1996.

School code: 0031.