A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

Abstract

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.

Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

“…Despite their small sample sizes, studies like these, and others of patients suffering from chronic cerebral circulation insufficiency (see You et al, 2019 for review), reflect a growing awareness that distinct temporal patterns of changes in blood oxygenation can trigger epigenetic responses in brain, and perhaps the immune system as well, that promote resilience to the progressive dementia suffered by individuals with AD and VCID. The evidence for environmental factors contributing to the genetic and nongenetic risk of AD and related dementias continues to grow (Finch & Kulminski 2019; Bertogliat et al, 2020; Burtscher et al 2021); despite the aforementioned studies on RLIC, recognition that the “exposome” can also promote disease resilience has yet to gain as strong of a foothold (Lourida et al, 2019; Dhana 2020; Vineis et al, 2020).…”

“…Ultimately, uncovering the proteomic, lipidomic, metabolomic, and other cellular- and regional (e.g., prefrontal cortex, hippocampus)- ‘omic features that define the dementia-resilient phenotype will be critical to the identification of specific downstream therapeutic effectors that protect against memory loss; that said, systemic treatments like RHC and RLIC that trigger multiple responses in tissues may be considered a ‘cocktail’ therapeutic that will not likely be mimicked by single molecule-targeted therapeutics. While extended periods of hypoxia can be pathologic, appropriately titrated intermittent hypoxia shows efficacy as a therapeutic for a number of diseases, without evidence of injury (Navarrette-Opazo 2014; Burtscher et al, 2021). In fact, we showed in our methylome study that even 4 months of RHC – twice the duration as used herein – did not adversely affect the viability of CA1 pyramidal cells, known to be the most sensitive neurons in the brain to hypoxia (Belmonte et al, 2020).…”

Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

“…As one example to achieve an enhanced resistance of the brain to hypoxic insults and inflammation, we recently provided rationales for the strengthening of brain resilience by hypoxia conditioning to counteract hypoxia-related brain insults in dementias [122], PD [31] and Huntington's disease [123]. While these neurodegenerative diseases certainly are characterized by distinct pathologies and metabolic abnormalities [124], the shared outcomes of dysregulated proteostasis and REDOX homeostasis, as well as mitochondrial deficits and neuroinflammation, suggest an involvement of the interplay of hypoxia, impaired pH and inflammatory processes in many of them.…”

Impact of High Altitude on Cardiovascular Health: Current Perspectives

“…110 Several systemic, brain-specific and cellular physiological adaptations are implemented to mitigate the detrimental consequences of hypoxia on the brain. [111][112][113][114][115][116][117][118][119] As described above, peripheral chemoreceptor-induced hyperventilation 120 and cardiac output 121,122 enhance systemic and brain oxygenation. Metabolic autoregulation and neurovascular coupling 95,123 acutely modulate the cerebral blood flow in response to hypoxia.…”

“…Although experimental data on hypoxia conditioning in patients with age-related neurological diseases is limited, the potential of such therapeutic strategies in these diseases is becoming increasingly acknowledged. 119,139,140 Preclinical studies in rodents further emphasize this potential, for example, in models of Alzheimer's disease 141,142 and Parkinson's disease. 143 Epidemiological studies on the effect of altitude of residence on brain function are conflicting, due in part to socioeconomic confounders.…”