Metabolomic Study of Hibernating Syrian Hamster Brains: In Search of Neuroprotective Agents

Abstract

Syrian hamsters undergo a reversible hyperphosphorylation of protein τ during hibernation, providing a unique natural model that may unveil the physiological mechanisms behind this critical process involved in the development of Alzheimer’s disease and other tauopathies. The hibernation cycle of these animals fluctuates between a pair of stages: 3–4 days of torpor bouts interspersed with periods of euthermia called arousals that last several hours. In this study, we investigated for the first time the metabolic changes in brain tissue during hibernation. A total of 337 metabolites showed statistically significant differences during hibernation. Based on these metabolites, several pathways were found to be significantly regulated and, therefore, play a key role in the regulation of hibernation processes. The increase in the levels of ceramides containing more than 20 C atoms was found in torpor animals, reflecting a higher activity of CerS2 during hibernation, linked to neurofibrillary tangle generation and structural changes in the Golgi apparatus. Our results open up the debate about the possible significance of some metabolites during hibernation, which may possibly be related to τ phosphorylation and dephosphorylation events. In general, this study may provide insights into novel neuroprotective agents because the alterations described throughout the hibernation process are reversible.

Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?

“…These adaptations are paralleled by significant changes in gene expression, which are thought to occur through differential control by transcription factors and chromatin remodeling [84,117,118,119]. These changes involve among other functions metabolism, response to hypoxia, DNA repair, cytoskeletal remodeling, and Ca 2+ signaling [120,121,122].…”

“…The majority of these studies have identified and quantified different CBPs in non-model species through Western blot and immunohistochemistry, comparing activity and hibernation periods both in terms of number of stained cells and the intensity of immunoreactivity. In more recent years, gene expression and proteomic analyses have opened the possibility for a more comprehensive understanding of life-cycle changes, including those associated with hibernation [121,124,125].…”

The Golgi Apparatus of Neocortical Glial Cells During Hibernation in the Syrian Hamster

“…In vitro experiments described significant morphological changes in the Golgi complex at low temperatures (15°C) (Martinez-Alonso et al, 2005). Hibernation can lead to biochemical adjustments to the membrane composition, such as an increase in the levels of ceramides containing more than 20 C atoms, which reportedly contributes to GA instability (Fukunaga et al, 2000; Gonzalez-Riano et al, 2019).…”

Human torpor: translating insights from nature into manned deep space expedition

“…Torpor is associated with a global change in various metabolites in the brain, indicating the existence of an intricate metabolic network during the torpor–arousal transition (Osborne & Hashimoto, 2008; Gonzalez‐Riano et al ., 2019). Energy is stored during torpor for future use during arousal, as indicated by higher levels of phosphorylated creatine in the brain (Lust et al ., 1989; Henry et al ., 2007).…”

“…Fine‐tuning of specific metabolites in different phases of torpor is not only required for the regulation of the torpor–arousal cycle, but also essential for innate neuroprotective mechanisms in hibernators. Fluctuations in inhibitory GABA and excitatory glutamate transmission in the brain have been suggested to work in concert to control metabolic suppression (Lust et al ., 1989; Henry et al ., 2007; Osborne & Hashimoto, 2008; Gonzalez‐Riano et al ., 2019). Nevertheless, contrary findings indicated that striatal extracellular GABA levels were higher in normothermic animals than animals in a torpid state (Osborne et al ., 1999).…”