Abstract 2014 Poster Session II, Sunday, 5/2 (poster 231)

Hypoxia-ischemia (HI) in newborns can cause brain damage and a variety of neurological abnormalities, including disorders in movement and posture. These motor disorders are thought to be due to damage to the basal ganglia after HI. The mechanisms for neuronal degeneration in the basal ganglia following HI in newborns are not understood. We used a piglet model of HI to test the hypothesis that defects in Na+,K+ ATPase occur during the progression of striatal neuron necrosis. Piglets (1 week old) were subjected to 30 minutes hypoxia (arterial oxygen saturation 30%) and then 7 minutes of airway occlusion (oxygen saturation 5%), producing asphyxic cardiac arrest, followed by cardiopulmonary resuscitation, return of spontaneous circulation, and then recovery for 3, 6, 12 or 24 hours (h). In this model of HI, the vulnerability of the putamen is much greater than that of the caudate nucleus (Martin et al, J. Comp. Neurol. 377:262-285, 1997). Neuronal injury in putamen evolves progressively after HI, with 16%, 31%, 47%, and 79% of neurons damaged at 3, 6, 12, and 24 h, respectively. By the electron microscopy and DNA fragmentation analysis, this neuronal degeneration is structurally and biochemically cellular necrosis (Martin et al, Ann. Neurol. 42:355-348, 1997; Martin et al, Brain Res. Bull. 46:281-309, 1998). HI causes time-dependent changes in Na+,K+ ATPase function, as determined by biochemical assay of Na+,K+ ATPase activity in homogenates of total striatum (caudate nucleus, putamen, nucleus accumbens, and internal capsule). Na+,K+ ATPase activity is 60%, 98%, 51%, and 54% of control at 3, 6, 12, and 24 h, respectively. Regionally differential changes in Na+,K+ ATPase function occur in the caudate nucleus and putamen after HI, as demonstrated by histochemical assay for plasma membrane surface-associated Na+,K+ ATPase in piglet brain sections. Before 12 h after HI, Na+,K+ ATPase activity is 73% of control in the caudate nucleus and 67% of control in the putamen. In both the caudate nucleus and putamen at 12 h after HI, Na+,K+ ATPase function recovers to normal levels (or exceeds control values, depending upon the region of caudate nucleus). In caudate nucleus, recovery of Na+,K+ ATPase activity is maintained after 12 h. In contrast, in putamen, Na+,K+ ATPase activity declines (66-78% of control) after 12 h recovery, with the most severe impairment in mid-central putamen. We conclude that delayed impairments in Na+,K+ ATPase function in putamen contribute to the mechanisms for striatal neuron necrosis during the first 24 h after HI in newborns, and that the inability to maintain recovery of Na+,K+ ATPase function may determine selective regional vulnerability to HI in newborns.

Funded by NIH NS20020 and NS34100.