The future of artificial hibernation medicine: protection of nerves and organs after spinal cord injury

Abstract

Spinal cord injury is a serious disease of the central nervous system involving irreversible nerve injury and various organ system injuries. At present, no effective clinical treatment exists. As one of the artificial hibernation techniques, mild hypothermia has preliminarily confirmed its clinical effect on spinal cord injury. However, its technical defects and barriers, along with serious clinical side effects, restrict its clinical application for spinal cord injury. Artificial hibernation is a future-oriented disruptive technology for human life support. It involves endogenous hibernation inducers and hibernation-related central neuromodulation that activate particular neurons, reduce the central constant temperature setting point, disrupt the normal constant body temperature, make the body "adapt" to the external cold environment, and reduce the physiological resistance to cold stimulation. Thus, studying the artificial hibernation mechanism may help develop new treatment strategies more suitable for clinical use than the cooling method of mild hypothermia technology. This review introduces artificial hibernation technologies, including mild hypothermia technology, hibernation inducers, and hibernation-related central neuromodulation technology. It summarizes the relevant research on hypothermia and hibernation for organ and nerve protection. These studies show that artificial hibernation technologies have therapeutic significance on nerve injury after spinal cord injury through inflammatory inhibition, immunosuppression, oxidative defense, and possible central protection. It also promotes the repair and protection of respiratory and digestive, cardiovascular, locomotor, urinary, and endocrine systems. This review provides new insights for the clinical treatment of nerve and multiple organ protection after spinal cord injury thanks to artificial hibernation. At present, artificial hibernation technology is not mature, and research faces various challenges. Nevertheless, the effort is worthwhile for the future development of medicine.

Keywords: artificial hibernation; central thermostatic-resistant regulation; hypothermia; multi-system protection; neuroprotection; organ protection; spinal cord injury; synthetic torpor.

Figure 1

Mechanism of the artificial hibernation-induced neuroprotection after spinal cord injury. Artificial hibernation may protect the nerves after spinal cord injury through the following aspects: i) Some unknown substances produced by the brain may directly protect the nerves during central thermostatic-resistant regulation. ii) Hypothermia inhibits the inflammatory reaction, reducing nerve cell damage. iii) Hypothermia can effectively reduce the transduction of intracellular inhibition signals and apoptosis signals, iv) protect mitochondria from apoptosis, v) maintain the stemness of neural stem cells and improve the tolerance of BMSC under adverse conditions, and vi) establish immunosuppressive and oxidative defense systems to reduce the injury caused by tissue reperfusion. vii) In vitro experimental studies showed that low temperatures can promote the growth of nerve axons and upregulate synaptic tissue genes. Created with Microsoft PowerPoint 2019. ANT: Adenine nucleotide translocator; BMSC: bone marrow mesenchymal stem cells; CD4⁺: CD4-positive T-lymphocytes; CD45RA⁺: CD45 naive/resting T-lymphocytes; CD8⁺: CD8-positive T-lymphocytes; CyPD: Cyclophilin-D; IL-10: interleukin-10; IL-1β: interleukin-1β; IL-6: interleukin-6; MPTP: mitochondrial permeability transition pore; NSC: neural stem cells; SUMO1: sumoylated-1 conjugated proteins; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α; WBC: white blood cell.

Figure 2

Artificial hibernation-induced protection of organs. Under artificial hibernation conditions, the body adopts an inflammatory inhibition state, reducing the harm caused by inflammation and protecting body organs and skeletal muscles. i) Respiratory and digestive system: there is an interactive relationship between the intestine, liver, and lung. During hibernation, intestinal microorganisms change and the levels of lymphocytes and pro-inflammatory factors increase, forming a strong immune barrier protection, preventing bacterial translocation into the blood after SCI, thus protecting the liver and fragile lungs. In addition, the release of lactate dehydrogenase in the liver is increased, which improves liver tolerance Besides, the increase of H₂S levels can reduce the body’s oxygen consumption and lung ventilation, further protecting the lung. ii) Under hibernation conditions, intracellular Ca²⁺ homeostasis enhances heart’s resistance to ventricular fibrillation. Hyperthermia can promote intermolecular signal transduction, thus maintaining contractile power. It can also slow down the cardiovascular damage caused by abnormal autonomic nerve reflex after SCI by blocking inflammation-related receptors. iii) Locomotor system: Ca²⁺ homeostasis is an important mechanism for maintaining the normal function of muscles under hibernation conditions, and hypothermia can actively protect the function and morphology of skeletal muscle cells. iv) Urinary system: artificial hibernation can reduce the damage caused by renal ischemia and reperfusion, and protect renal function and tissue structure. Created with Microsoft PowerPoint 2019. ATP: Adenosine 5′ triphosphate; HSP-70: heat shock protein-70; IFN-γ: interferon γ; IL-10: interleukin-10; IL-6: interleukin-6; LDH: lactate dehydrogenase; SUMO1: sumoylated-1 conjugated proteins; TNF-α: tumor necrosis factor-α; UCP-3: uncoupling protein-3.