Neuroprotective effect of indomethacin in normal perfusion pressure breakthrough phenomenon

Abstract

Loss of cerebral autoregulation in normal perfusion pressure breakthrough (NPPB) phenomenon has been reported in other Central Nervous System diseases such as neonatal intraventricular haemorrhage. Several studies have demonstrated that low-dose indomethacin prevents this latter condition. A previous rat model was used to resemble NPPB phenomenon. Study animals were distributed in 4 groups that received 3 doses of indomethacin at different concentrations prior to fistula occlusion 60 days after its creation. Control animals received saline solution. Intracranial pressure (ICP) increased in all groups following fistula creation, whereas mean arterial pressure (MAP) and cerebral perfusion pressure (CPP) decreased as a manifestation of cerebral hypoperfusion and intracranial hypertension. The administration of indomethacin was associated with raised MAP and CPP, as well as decreased ICP. Sodium fluorescein extravasation was slight in study animals when comparing with control ones. Histological analysis evidenced diffuse ischaemic changes with signs of neuronal apoptosis in all brain layers in control animals. These findings were only focal and slight in study animals. The results suggest the usefulness of indomethacin to revert, at least partially, the haemodynamic effects of NPPB phenomenon in this experimental model, as well as to reduce BBB disruption and histological ischemia observed in absence of indomethacin.

Figure 1

Flow chart of surgical procedures and variable measurements in study and control groups during the experiment.

Figure 2

(a,c,e) Distribution of MAP, ICP and CPP in all groups, represented as the median. (b,d,f) Linear predictions of MAP, ICP and CPP in accordance to time with their respective 95% confidence interval.

Figure 3

Rat brain photograph of control and study groups. Sodium fluorescein extravasation is evidenced. Staining is lighter in those specimens that had previously received indomethacin when comparing with control specimen.

Figure 4

Light microscopy (haematoxylin and eosin staining): comparison between control and study groups (labelled by indomethacin dose received) at different augmentation.