Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

 This is interesting because almost all other research works on delivering more oxygen to the brain. Ask your doctor to reconcile. Can both be done at different times?

• supersaturated oxygen therapy (1)

• cortical oxygenation (1)

• Extracorporeal membrane oxygenation (2)

• Normobaric oxygen (12)

• oxygen (17)

• oxygen delivery (11)

• oxygen saturation (1)

• oxygen therapy (2)

• oxygen uptake (5)

Exploring How Low Oxygen Post Conditioning Improves Stroke-Induced Cognitive Impairment: A Consideration of Amyloid-Beta Loading and Other Mechanisms

Zidan Zhao^1,2,3, Rebecca J. Hood^1,2,3, Lin Kooi Ong^1,2,3,4,5, Giovanni Pietrogrande^1,2,3, Sonia Sanchez Bezanilla^1,2,3, Kirby E. Warren^1,2,3, Marina Ilicic^1,2,3, Murielle G. Kluge^1,2,3, Clifford TeBay^1,2,3, Ole P. Ottersen^6,7, Sarah J. Johnson^8,9, Michael Nilsson^2,3,4,9† and Frederick R. Walker^{1,2,3,4,9*†}

• ¹School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
• ²Priority Research Centre for Stroke and Brain Injury, University of Newcastle, Newcastle, NSW, Australia
• ³Hunter Medical Research Institute, Newcastle, NSW, Australia
• ⁴National Health and Medical Research Council Centre of Research Excellence in Stroke Rehabilitation and Brain Recovery, Heidelberg, VIC, Australia
• ⁵School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
• ⁶Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
• ⁷Office of the President, Karolinska Institutet, Stockholm, Sweden
• ⁸School of Electrical Engineering and Computing, University of Newcastle, Newcastle, NSW, Australia
• ⁹Centre for Rehab Innovations, University of Newcastle, Newcastle, NSW, Australia

Cognitive impairment is a common and disruptive outcome for stroke survivors, which is recognized to be notoriously difficult to treat. Previously, we have shown that low oxygen post-conditioning (LOPC) improves motor function and limits secondary neuronal loss in the thalamus after experimental stroke. There is also emerging evidence that LOPC may improve cognitive function post-stroke. In the current study we aimed to explore how exposure to LOPC may improve cognition post-stroke. Experimental stroke was induced using photothrombotic occlusion in adult, male C57BL/6 mice. At 72 h post-stroke animals were randomly assigned to either normal atmospheric air or to one of two low oxygen (11% O₂) exposure groups (either 8 or 24 h/day for 14 days). Cognition was assessed during the treatment phase using a touchscreen based paired-associate learning assessment. At the end of treatment (17 days post-stroke) mice were euthanized and tissue was collected for subsequent histology and biochemical analysis. LOPC (both 8 and 24 h) enhanced learning and memory in the 2nd week post-stroke when compared with stroke animals exposed to atmospheric air. Additionally we observed LOPC was associated with lower levels of neuronal loss, the restoration of several vascular deficits, as well as a reduction in the severity of the amyloid-beta (Aβ) burden. These findings provide further insight into the pro-cognitive benefits of LOPC.

Introduction

Cognitive impairment has been reported as one of the most debilitating side-effects of stroke, impacting up to 80% of survivors (1, 2). Problems with memory, learning, and attention can significantly impact a survivor's functional independence and several studies have reported that increased levels of cognitive impairment are associated with lower levels of self-reported quality of life (3). This situation has triggered a substantial effort both clinically and pre-clinically to develop effective strategies to improve cognitive function post-stroke (4, 5).

Currently, there are no approved therapeutic interventions for post-stroke cognitive impairment. Although promising, the use of individual pharmacological strategies e.g., donepezil and memantine, have a patchy record of success (2). Recent evidence has shown pro-cognitive effects of exogenously delivered growth hormone post-stroke (6–9). Another equally promising pro-cognitive therapy has been the use of intermittent exposure to a reduced oxygen environment (10, 11). This non-pharmacological approach has numerous advantages over current strategies including its well-characterized and acceptable safety-profile, relatively low cost, ease of delivery and scalability.

In the context of stroke, exposure to a low oxygen environment prior to induction of an ischemic event (up to and including 4 weeks prior) has been shown to produce robust neuroprotection (10). Whilst the exposure to low oxygen prior to an ischemic event is of interest, exposure post ischemic event is arguably a more translationally relevant time to evaluate. In this context, low oxygen post-conditioning (LOPC) has been demonstrated to exhibit significant therapeutic properties in the context of heart attack (12) and spinal cord injury (13) and there is a growing body of evidence to support its application post-stroke (14–19). Preclinical studies have shown LOPC to be neuroprotective (15), enhance neurogenesis (18, 19), and reduce the severity of secondary neuronal loss and atrophy in the thalamus (14, 17). LOPC has also been shown to improve motor function (15) and cognition (18, 19).

Despite evidence indicating the potential utility of LOPC as a therapy, the underlying mechanisms involved in driving the positive post-stroke exposure outcomes are relatively unknown. We have recently identified a number of mechanisms that correlate with post-stroke cognitive impairment including loss of neural tissue and vasculature, the accumulation of neurotoxic proteins including amyloid-beta (Aβ) (20), vascular leakage and aquaporin four (AQP4) depolarization (associated with effective clearance of neurotoxic proteins) (20). It is clear that post-stroke exposure to LOPC promotes neuronal survival and vascular growth (14, 15, 17), yet what remains unclear is whether LOPC improves other aspects of vascular function (i.e., AQP4 polarization), or whether these improvements can modulate the Aβ burden. Therefore, in this study we sought to consider whether LOPC influenced these mechanisms. We have also considered the impact of LOPC on several genes involved in regulating the expression of Aβ including production of Aβ [amyloid precursor protein (APP) (21); beta secretase enzyme−1 (BACE) (22); tumor necrosis factor α (TNFα) converting enzyme (TACE) (23)], transport of Aβ across the blood-brain barrier into the parenchyma [receptor for advanced glycation end products (RAGE) (24)], Aβ degrading enzymes [neprilysin (NEP) (25), endothelin-converting enzyme (ECE) (26) and insulin-degrading enzyme (IDE) (25)] and clearance of Aβ [low-density lipoprotein receptor-related protein 1 (LRP1) (27–29)].