Hypobaric hypoxia causes atmospheric pressure aberrations which results in increased radical generation in the mitochondrial electron transport chain. The oft witnessed sites for the most damage due to oxidative stress are the lungs and brain. Their heightened susceptibility is also reflected in the high-altitude ailments like AMS, HACE (affecting the brain) and HAPE (affecting the lungs). This is a well-accepted conclusion that oxidative stress and associated inflammatory processes are the underlying cause of these patho-physiologies. Across various disciplines and domains, many endeavors have been undertaken for the resolution of these underlying causes. These range from exposure to hypoxia mimetics (e.g.- Cobalt chloride) to increased administration of plant extracts with anti-oxidant potential (e.g.- Gingko biloba). Nanoceria present a promising choice.
Based on emerging data and studies from around the globe, we hypothesized that nanoceria may have exemplary effects against hypobaric hypoxia induced oxidative stress. To this end, we synthesized spherical nanoceria particles (7-10 microns diameter) using microemulsion technology. These spherical nanoceria were then administered intra-peritoneally to male SD rats on a weekly basis for 5 weeks. Their lung tissue was harvested after an acute hypobaric hypoxia exposure at 25,000 ft (simulated). We observed nanoceria deposited in lung tissue and was effective at reducing ROS formation (possibly by quenching of radicals), glutathione oxidation, nitrosylation and carbonylation as well as inflammatory processes. Spherical nanoceria were already known to protect cells against oxidative damage. However, their effects on mitochondrial membrane potential (MMP) were not known. Thus, we cultured primary cortical cells from SD pups (1 day old) and challenged this cortical culture with high concentrations of hydrogen peroxide. Upon nanoceria application, we observed lowered ROS and calcium flux in the culture. Moreover, nanoceria caused maintenance of MMP, restoration of NAD/NADH ratio and cellular ATP. All these together led to increased cell viability and reduced apoptosis (Published in International Journal of Nano-medicine). It hints at nanoceria as an effective agent in protecting brain against oxidative stress. But nanoceria have poor permeability through blood-brain barrier. To overcome this drawback, we formulated a polyethyleneglycol (PEG) coating of nanoceria (PEG-CNP). The PEG-CNP efficiently localized in rodent brain. We observed it not only abrogated oxidative stress but also prevented hypoxia induced loss of memory based cognitive function by augmenting neuronal survival. Another astonishing finding was the ability of PEG-CNPs to promote neurogenesis. We determined this neurogenesis to be the result of PEG-CNPs modulation AMPK-PKC-CBP pathway.
Nanoceria has proven beneficial effects in both lungs and brain while NAP is the most potent anti-oxidant for preventing oxidative damage in the brain. However, the ability of nanoceria (as PEG-CNPs) to promote neurogenesis is truly unique.
NAP as another potential protective agent
Another agent with similar effects is NAP, an octapeptide with initial amino acids: asparagine/N, alanine/A, and proline/P, derived from Activity dependent neuroprotective protein. It has already been proven to have considerable activity at femtomolar concentrations and high-permeability through the blood-brain barrier. In our study we posit the changes in antioxidant genes’ profile and associated cell death in a primary hippocampal culture in response to 72h of hypoxia after administration of 15fM NAP. In addition to reduced cell death during hypoxia, NAP modulates multiple antioxidant genes. The most significant among them, however, is augmentation of hydrogen peroxide scavenging system consisting of catalase, peroxiredoxins and glutathione reductases and peroxidases.
To conclude, nanoceria has proven beneficial effects in both lungs and brain while NAP is the most potent anti-oxidant for preventing oxidative damage in the brain. However, the ability of nanoceria (as PEG-CNPs) to promote neurogenesis is truly unique. In the near future, a hybrid consisting of the advantages conferred by both agents can lead to the perfect prophylactic against hypoxia induced oxidative stress and its related patho-physiologies.
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