Cerebellum Susceptibility to Neonatal Asphyxia: Possible Protective Effects of N-Acetylcysteine Amide

Abstract

Background After perinatal asphyxia, the cerebellum presents more damage than previously suggested. Objectives To explore if the antioxidant N-acetylcysteine amide (NACA) could reduce cerebellar injury after hypoxia-reoxygenation in a neonatal pig model. Methods Twenty-four newborn pigs in two intervention groups were exposed to 8% oxygen and hypercapnia, until base excess fell to −20 mmol/l or the mean arterial blood pressure declined to <20 mmHg. After hypoxia, they received either NACA (NACA group, n = 12) or saline (vehicle-treated group, n = 12). One sham-operated group (n = 5) served as a control and was not subjected to hypoxia. Observation time after the end of hypoxia was 9.5 hours. Results The intranuclear proteolytic activity in Purkinje cells of asphyxiated vehicle-treated pigs was significantly higher than that in sham controls (p = 0.03). Treatment with NACA was associated with a trend to decreased intranuclear proteolytic activity (p = 0.08), There were significantly less mutations in the mtDNA of the NACA group compared with the vehicle-treated group, 2.0 × 10−4 (±2.0 × 10−4) versus 4.8 × 10−5(±3.6 × 10−4, p < 0.05). Conclusion We found a trend to lower proteolytic activity in the core of Purkinje cells and significantly reduced mutation rate of mtDNA in the NACA group, which may indicate a positive effect of NACA after neonatal hypoxia. Measuring the proteolytic activity in the nucleus of Purkinje cells could be used to assess the effect of different neuroprotective substances after perinatal asphyxia.

Growth Hormone (GH) Crosses the Blood–Brain Barrier (BBB) and Induces Neuroprotective Effects in the Embryonic Chicken Cerebellum after a Hypoxic Injury

“…Lee et al, (2001) [ 9 ], demonstrated that, in chick embryos, chronic hypoxia (from ED2 to ED21) hinders the normal development of Purkinje cells marked by small cell size, poorly developed dendrites, low cell density, and ectopia. Similar findings were reported in the developing mammalian cerebellum [ 4 , 33 , 34 ]. Biran et al, (2011) [ 4 ], described a decrease in the number of Purkinje cells, granular neurons, and interneurons as well as in the thickness of molecular (ML) and granular (GL) layers in two-day-old rat pups exposed to global hypoxia or hypoxic-ischemia injury.…”

“…The high susceptibility of Purkinje cells to hypoxia may be associated with their high metabolic demand and elaborated synaptic interactions [ 34 ]. The ectopic distribution of Purkinje cells has been reported in some mutant mice with cerebellar abnormalities, e.g., reel mice [ 33 ] and normal rodents [ 35 ]. Thus, our results support the notion that hypoxia disturbs the migration of Purkinje cells on their way to the cerebellar cortex.…”

Dual isolation of primary neurons and oligodendrocytes from guinea pig frontal cortex

“…Progress has been made in sustaining cerebellar cultures from GA62 fetal guinea pigs using a slightly modified protocol. This brain region is chosen for its high affinity for damage following perinatal insult (Kwan et al, 2015 ; Benterud et al, 2018 ). We further suggest that this protocol could further be adapted to establish cultures from other brain regions such as the hippocampus, further decreasing tissue wastage and improving the relevance of this protocol for investigating perinatal insults that often affect these areas.…”