Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

Abstract

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI.

Stress‐induced autonomic dysregulation of mitochondrial function in the rat urothelium

“…Exploring different facets of mitochondrial function should provide new insights as to how mitochondria may hold the key to “cellular memory” long after a stressor is removed or ceases. Clinically, ROS scavengers such as Tempol and the specific mitochondria targeted compound XJB‐5‐131 have shown structural and functional improvements in animal models of spinal cord and traumatic brain injury, Huntington's, aging muscle contractility and others . Moreover, Tempol is safe in humans .…”

Dexmedetomidine attenuates neuronal injury after spinal cord ischaemia‐reperfusion injury by targeting the CNPY2‐endoplasmic reticulum stress signalling

“…Many studies have shown that transient ischaemia and hypoxia can cause spinal nerve necrosis . The primary mechanisms whereby this occurs include free radical and lipid peroxidation, intracellular calcium disruption, release of inflammatory factors, excitatory neurotransmitter damage, apoptosis of nerve cells and a series of pathophysiological processes . Continual ischaemia and hypoxia can aggravate SCIRI, resulting in secondary oedema of the spinal cord and increased intrathecal pressure, potentially leading to increased tissue damage and aggravated loss of motor function.…”

“…31 The primary mechanisms whereby this occurs include free radical and lipid peroxidation, intracellular calcium disruption, release of inflammatory factors, excitatory neurotransmitter damage, apoptosis of nerve cells and a series of pathophysiological processes. [3][4][5][6] Continual ischaemia and hypoxia can aggravate SCIRI, resulting in secondary oedema of the spinal cord and increased intrathecal pressure, potentially leading to increased tissue damage and aggravated loss of motor function. At F I G U R E 4 Dex pre-treatment effectively attenuates the expression level of CNPY2 and GRP78 mRNA on ER of spinal cord induced by SCIRI.…”

“…The pathogenesis of SCIRI is complex, and the specific mechanism of spinal cord death in response to reperfusion is not clear. Studies have shown that spinal cord ischaemia and reperfusion may be related to excitotoxicity, immunologic injury, disturbances in mitochondrion function and apoptosis . Although significant progress has been made in the treatment of spinal ischaemic injury in recent years, SCIRI remains a major unresolved issue.…”

“…Studies have shown that spinal cord ischaemia and reperfusion may be related to excitotoxicity, immunologic injury, disturbances in mitochondrion function and apoptosis. [3][4][5][6] Although significant progress has been made in the treatment of spinal ischaemic injury in recent years, SCIRI remains a major unresolved issue. Identifying new drugs or new methods to protect and save injured spinal cord tissue is important for treatment of this pathology.…”