Introduction
There is evidence that hypothermia has neuro-protective effects in hypoxia-ischemic brain injury. However, the magnitude and duration of hypothermia necessary to produce the most benefit is unclear; similarly, the optimum therapeutic window for hypothermia to be effective is unknown. Whether hypothermia ameliorates brain pathology temporarily and delays the re-perfusion injury, or leads to long-lasting benefits needs to be shown.

We hypothesized: 1) early treatment with hypothermia after neonatal H-I injury is superior to later implementation; and 2) the effects of hypothermia can be demonstrated during infancy in the form of neurological deficit and learning and memory functions.

Methods
We used a modified Levine model of 7-days-old rat pups from two litters (total n=21) in which unilateral common carotid artery ligation was done under anesthesia and, one hour later, hypoxic breathing with 8% O2 for 120 min was instigated.

Treatment groups: Group 1: Controls with no H-I insult; Group II: HIE insult but no treatment; Group III: Early hypothermia [EH: 15 min following HI insult, the body temperature reduced to 32°C for 3 hrs; and Group IV: Late hypothermia [LH: 60 min following HI, the body temperature was reduced to 32°C for three hours].

Outcomes: 1) Daily neurological testing for 9 days; 2) Learning and memory tests (at 4, 6 and 8 weeks) using the Morris water maze (MWM) with a video monitoring and motion tracking computer system (EthoVision, Noldus Information Technology); and 3) Radial arm maze (RAM: trained at 9^th week, and tested on the 10^th week). The animals were killed 60 days after HI injury (~67 days of age).

Results

Table 1. Mean+/- SD for various behavioral measures.

Summary
1) Significant impairment in learning and memory was seen in our HI model, which was not due to neuromuscular dysfunction, 2) MWM tests revealed slightly improved long-term memory and learning at 30 days in the hypothermic groups, but the effects were modest and not sustained; no differences were noted on day 60 of age. 4) Considerable variability in outcomes was noted on learning/memory tests.

Conclusions
In this model of HI insult causes impairment of learning and memory, which was not due to neuromuscular dysfunction. Hypothermia might provide a transient benefit, however by 60 days these improvements are not sustained. 3) Early hypothermia may be more effective than late hypothermia; however, more studies should be done to evaluate the effect of the timing, duration and dosage of hypothermia on HIE.

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