Hypothermia is not neuroprotective after infection-sensitized neonatal hypoxic-ischemic brain injury

Background: Therapeutic hypothermia (HT) is the standard treatment after perinatal hypoxic-ischemic (HI) injury. Infection increases vulnerability to HI injury, but the effect of HT on lipopolysaccharide (LPS) sensitized HI brain injury is unknown.

Design/methods: P7 rat pups were injected either with vehicle or LPS, and after a 4h delay they were exposed to left carotid ligation followed by global hypoxia inducing a unilateral stroke-like HI injury. Pups were randomized to the following treatments: (1) vehicle treated HI-pups receiving normothermia treatment (NT) (Veh-NT; n=30); (2) LPS treated HI-pups receiving NT treatment (LPS-NT; n=35); (3) vehicle treated HI-pups receiving HT treatment (Veh-HT; n=29); or (4) LPS treated HI-pups receiving HT treatment (LPS-HT; n=46). Relative area loss of the left/right hemisphere and the areas of hippocampi were measured at P14.

Results: Mean brain area loss in the Veh-NT group was 11.2±14%. The brain area loss in LPS-NT pups was 29.8±17%, which was significantly higher than in the Veh-NT group (p=0.002). The Veh-HT group had a significantly smaller brain area loss (5.4±6%), when compared to Veh-NT group (p=0.043). The LPS-HT group showed a brain area loss of 32.5±16%, which was significantly higher than in the Veh-HT group (p<0.001). LPS-HT group also had significantly smaller size of the left hippocampus, which was not found in other groups. LPS-sensitization significantly decreased the sizes of the right, unligated-hemispheres, independent of post-HI treatment.

Conclusions: Therapeutic hypothermia is not neuroprotective in this LPS-sensitized unilateral stroke-like HI brain injury model in newborn rats. Lack of neuroprotection was particularly seen in the hippocampus. Pre-insult exposure to LPS also induced brain area loss in the unligated hemisphere, which is normally not affected in this model.