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Polydatin Attenuates OGD/R-Induced Neuronal Injury and Spinal Cord Ischemia/Reperfusion Injury by Protecting
Jiheng Zhan1,2,3,4, Xing Li1,2,3, Dan Luo1,2,3
1Department of Spine Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China.
Abstract:
Spinal cord ischemia/reperfusion injury (SCII) is a devastating complication of spinal or thoracic surgical procedures and can lead to paraplegia or quadriplegia. Neuronal cell damage involving mitochondrial dysfunction plays an important role in the pathogenesis of SCII. Despite the availability of various treatment options, there are currently no mitochondria-targeting drugs that have proven effective against SCII. Polydatin (PD), a glucoside of resveratrol, is known to preserve mitochondrial function in central nervous system (CNS) diseases. The aim of the present study was to explore the neuro- and mito-protective functions of PD and its underlying mechanisms. An in vitro model of SCII was established by exposing spinal cord motor neurons (SMNs) to oxygen-glucose-deprivation/reperfusion (OGD/R), and the cells were treated with different dosages of PD for varying durations. PD improved neuronal viability and protected against OGD/R-induced apoptosis and mitochondrial injury in a dose-dependent manner. In addition, PD restored the activity of neuronal mitochondria in terms of mitochondrial membrane potential (MMP), intracellular calcium levels, mitochondrial permeability transition pore (mPTP) opening, generation of reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels. Mechanistically, PD downregulated Keap1 and upregulated Nrf2, NQO-1, and HO-1 in the OGD/R-treated SMNs. Likewise, PD treatment also reversed the neuronal and mitochondrial damage induced by SCII in a mouse model. Furthermore, the protective effects of PD were partially blocked by the Nrf2 inhibitor. Taken together, PD relieves mitochondrial dysfunction-induced neuronal cell damage by activating the Nrf2/ARE pathway and is a suitable therapeutic option for SCII.
Insights
Polydatin (PD) protects spinal cord motor neurons from injury by preserving mitochondrial function and activating the Nrf2/ARE pathway, offering a potential therapy for spinal cord ischemia/reperfusion injury (SCII).
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- Spinal cord ischemia/reperfusion injury (SCII) can cause severe neurological deficits like paralysis.
- Mitochondrial dysfunction is a key factor in SCII pathogenesis.
- Effective mitochondria-targeting therapies for SCII are lacking.
Purpose of the Study:
- To investigate the neuroprotective and mitochondria-protective effects of Polydatin (PD) against SCII.
- To elucidate the underlying mechanisms of PD's action, particularly its impact on the Nrf2/ARE pathway.
Main Methods:
- Established an in vitro SCII model using oxygen-glucose-deprivation/reperfusion (OGD/R) of spinal cord motor neurons (SMNs).
- Treated SMNs and a mouse model of SCII with varying doses of PD.
- Assessed neuronal viability, apoptosis, mitochondrial function (MMP, calcium, mPTP, ROS, ATP), and Nrf2/ARE pathway activation.
Main Results:
- PD dose-dependently improved neuronal viability and reduced apoptosis and mitochondrial injury in vitro.
- PD restored mitochondrial function by normalizing MMP, calcium levels, mPTP opening, ROS production, and ATP levels.
- PD activated the Nrf2/ARE pathway (downregulating Keap1, upregulating Nrf2, NQO-1, HO-1) and showed protective effects in a mouse SCII model.
Conclusions:
- Polydatin (PD) effectively protects against neuronal and mitochondrial damage in SCII.
- PD exerts its protective effects by activating the Nrf2/ARE pathway, mitigating mitochondrial dysfunction.
- PD represents a promising therapeutic candidate for treating spinal cord ischemia/reperfusion injury.
