Neuroprotection: Lessons from hibernators

Dave, Kunjan R.; Christian, Sherri L.; Pérez-Pinzón, Miguel A.; Drew, Kelly L.

doi:10.1016/j.cbpb.2012.01.008

Cited by 99 publications

(88 citation statements)

References 139 publications

(197 reference statements)

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“…SUMOylation plays an important role in neuroprotection in models of hibernation and ischemia tolerance. Hibernators naturally tolerate severe reductions in cerebral blood flow during torpor [51,52]. For example, our laboratory previously observed that arctic ground squirrels (Urocitellus parryii) are remarkably tolerant to global cerebral ischemia during euthermia [53,54].…”

Section: Sumoylationmentioning

confidence: 99%

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

et al. 2013

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Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain's ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.

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Section: Sumoylationmentioning

confidence: 99%

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

et al. 2013

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“…During hibernation, it is stressful for cells to be exposed to low temperatures for long periods because of its effects on processes such as protein stability, membrane function, ATP synthesis, activity of key regulatory enzymes and cytoskeletal integrity (Kandror and Goldberg, 1997;Sonna et al, 2002). Additionally, ischemia-induced oxidative stress during hibernation is considered to play a crucial role in cell death (Dave et al, 2012). Because of the high risk of cell death, increased cell proliferation might be an important protective mechanism for hibernating mammals to cope with potential cell damage during hibernation.…”

Section: Introductionmentioning

confidence: 99%

Gene expression and adaptive evolution of ZBED1 in the hibernating great horseshoe bat (Rhinolophus ferrumequinum)

Xiao

Sun

et al. 2016

Journal of Experimental Biology

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Mammalian hibernators experience physiological extremes, e.g. ischemia, muscle disuse and hypothermia, which are lethal to nonhibernators, implying the existence of underlying mechanisms that allow hibernators to withstand these physiological extremes. Increased cell proliferation is suggested to be such a strategy, but its molecular basis remains unknown. In this study, we characterized the expression pattern of ZBED1 (zinc finger, BED-type containing 1), a transcription factor that plays a crucial role in regulating cell proliferation, in five tissues of the greater horseshoe bat (Rhinolophus ferrumequinum) during pre-hibernation, deep hibernation and post-hibernation. Moreover, we investigated the ZBED1 genetic divergence from individuals with variable hibernation phenotypes that cover all three known mtDNA lineages of the species. Expression analyses showed that ZBED1 is overexpressed only in brain and skeletal muscle, not in the other three tissues, suggesting an increased cell proliferation in these two tissues during deep hibernation. Evolutionary analyses showed that ZBED1 sequences were clustered into two well-supported clades with each one dominated by hibernating and non-hibernating individuals, respectively. Positive selection analyses further showed some positively selected sites and a divergent selection pressure among hibernating and non-hibernating groups of R. ferrumequinum. Our results suggest that ZBED1 as a potential candidate gene that regulates cell proliferation for hibernators to face physiological extremes during hibernation.

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“…However, in spite of this balance, cytoarchitectural signs of changed functional activity occurred in March, as shown also after GAD67, PV and pNF-H immunoreactions. On the other hand, previous immunohistological studies in ground squirrels demonstrate a 50-65% loss of synapses over the entire brain during entry into torpor (Von Der Ohe et al 2007;Osborne & Hashimoto 2008;Dave et al 2012). Beyond this, the length and branching of the dendritic arbor as well as the number of dendritic spines are decreased in the hippocampus (Popov et al , 2007von der Ohe et al 2007), thalamus and cortex (Popov et al 2007;Ruediger et al 2007).…”

Section: Intracellular Calcium Homeostasismentioning

confidence: 87%

“…Furthermore, cytoskeletal reorganisation is known to occur on return to euthermy (Dave et al 2012). Neural retraction across multiple brain regions has been described: dendritic spines and synaptic profiles shrink, accompanied by general cytoskeletal breakdown as microtubules disassemble.…”

Section: The Cytoskeletonmentioning

confidence: 99%

“…However, hibernators can survive both frequent and dramatic fluctuations of body temperature and blood flow, caused by periodic arousals, without any signs of neurological damage (Frerichs et al 1994;Frerichs 1999), as well as in experimental conditions against neurological insults (Frerichs et al 1994;Frerichs & Hallenbeck 1998;Frerichs 1999;Zhou et al 2001Zhou et al , 2002. Notably, the hibernating mammal brain, which has a central regulatory role in the hibernation (Drew et al 2007), is protected against a variety of insults detrimental to humans and other non-hibernating species Dave et al 2012). Specific brain areas remain active during deep torpor (Heller 1979), even when the hibernator's body temperature drops close to the freezing point of water and the brain becomes electrically quiescent to surface electroencephalography (Heller & Ruby 2004).…”

Section: Introductionmentioning

confidence: 99%

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Changes in the cerebellar cytoarchitecture of hibernating hedgehogErinaceus europaeusL. (Mammalia): an immunocytochemical approach

Roda

Bottone

Insolia

et al. 2017

The European Zoological Journal

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Hibernation is an amazing animal strategy to survive when the environmental temperature is very low and food resources are scarce. Successful hibernation requires a variety of complex biological adaptations, in which the brain plays a central regulatory role. Currently, little information is available regarding the morphology and functional activity of specific neurons within the cerebellar cytoarchitecture of hibernating animals. In the present study, we investigated the immunohistochemical expression of essential proteins in the cerebellum of a mammalian hibernator (i.e. hedgehog Erinaceus europaeus L.), focusing on (i) Purkinje neurons, the sole output cells of the cerebellar cortex; (ii) selected neurotransmitters involved in hibernation processes; (iii) intracellular calcium homeostasis, considering that calcium is also an important regulator of neurotransmission mechanisms; and (iv) cytoskeletal proteins, involved in maintenance of neuronal shape and axon calibre. Specifically, we studied in situ immunocytochemical changes during the torpor state of hibernation (November-March) versus the activity phase (AprilSeptember). We employed different selected markers, i.e. glutamic acid decarboxylase (GAD67) and postsynaptic glutamate ionotropic receptor GluR2-3, different calcium-binding proteins (i.e. calbindin, parvalbumin and calretinin) and cytoskeletal components (i.e. pNF-H and MAP2). In summary, our data in hibernating animals demonstrated: (i) downregulation of GAD67, indicating loss/changes of synaptic contacts on Purkinje somata and dendrites; (ii) GluR2-3 upregulation in Purkinje neurons, with a drastic decrease of calbindin expression; and (iii) decrease of normal mechanisms regulating intracellular calcium homeostasis. We also found a decrease/modification in the distribution of cytoskeletal proteins, particularly evident for pNF-H. Changes in the functional activity of Purkinje cells were accompanied by some morphological dendrite alterations, signs of degeneration in cell somata and flattened basket pinceaux at the Purkinje axon hillock. These findings confirm that hibernation makes heterothermic animals a valuable model to study physiological adaptations to adverse conditions, and also for understanding cellular and molecular mechanisms aimed at preserving mammalian organs from full degeneration and death.

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Neuroprotection: Lessons from hibernators

Cited by 99 publications

References 139 publications

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

Gene expression and adaptive evolution of ZBED1 in the hibernating great horseshoe bat (Rhinolophus ferrumequinum)

Changes in the cerebellar cytoarchitecture of hibernating hedgehogErinaceus europaeusL. (Mammalia): an immunocytochemical approach

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