A novel translocator protein 18 kDa ligand, ZBD‐2, exerts neuroprotective effects against acute spinal cord injury

Cheng, Qiang; Sun, Guojing; Liu, Shui-bing; Yang, Qi; Li, Xiaoming; Li, Xubo; Liu, Gang; Zhao, Jianning; Zhao, Ming

doi:10.1111/1440-1681.12606

Cited by 8 publications

(5 citation statements)

References 47 publications

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“…A TSPO ligand, ZBD‐2, was found to significantly decrease necrosis following middle cerebral artery occlusion in a mouse model (Li et al, ). The same TSPO ligand was found to decrease oxidative stress following traumatic spinal cord injury in mice (Cheng et al, ), further alluding to TSPO's role in the regulation of ROS. Other studies have shown that Ro5‐4864 and PK 11195 also increase ROS and reactive microglia accumulation (Choi et al, 2011).…”

Section: Strokementioning

confidence: 93%

TSPO regulation in reactive gliotic diseases

McNeela

Bernick

Hines

et al. 2018

J of Neuroscience Research

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The brain is the most metabolically active organ in the body. This high metabolic demand is apparent in that 60% of the brain is comprised of mitochondria-enriched cells. A disruption of the brain's ability to meet this immense metabolic demand is central to the pathogenesis of a multitude of neurological disorders, which range from depression to Alzheimer's disease. Central to these pathologies are glial signaling and energy metabolism cascades regulating apoptosis and inflammation. Thus, diseases causing inflammation and disruption of metabolism can be correlated with glial reactivity. Acutely, reactive gliosis provides a mechanism for limiting the progression of a disease. Following chronic activation, the ability of reactive gliosis to limit disease progression decreases and, in some cases, transitions into a harmful state. The necessity for a noninvasive biomarker of disease in the brain has linked reactive gliosis with an upregulation of translocator protein (TSPO). TSPO is an 18kDa protein that is both a therapeutic target for multiple acute and chronic neuroinflammatory diseases and the leading biomarker for Alzheimer's disease. Although a central function of TSPO is not well known, the protein was named for its ability to translocate cholesterol. Increased TSPO expression is an indicator of disrupted metabolic activity and increased reactive oxygen production. The changes in TSPO expression levels both temporally and spatially relate to the pathogenesis of stroke, Alzheimer's disease, traumatic brain injury, and depression. Therefore, research into the basic function and potential therapeutics targeting TSPO will have broad implications for many diseases of the brain.

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Section: Strokementioning

confidence: 93%

TSPO regulation in reactive gliotic diseases

McNeela

Bernick

Hines

et al. 2018

J of Neuroscience Research

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“…2-Cl-MGV also rescued cognitive impairments and neuronal loss after injury compared to vehicle controls [79]. In a mouse model of spinal cord injury, administration of the TSPO ligand ZBD-2 following injury downregulated TSPO expression, reduced levels of inducible nitric oxide synthase (iNOS) and malondialdehyde (MDA), and increased levels of superoxide dismutase (SOD) in serum, whilst also reducing neuronal loss after injury [80], hence having antioxidative properties. It is therefore apparent that there is much emerging literature surrounding the role of TSPO in mitochondrial processes, including energy metabolism and ROS generation ( Table 1).…”

Section: In Vivo Evidence For Tspo In Mitochondrial Processesmentioning

confidence: 99%

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

Betlazar

Middleton

Bánati

et al. 2020

Cells

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The translocator protein (TSPO) is an outer mitochondrial membrane protein that is widely used as a biomarker of neuroinflammation, being markedly upregulated in activated microglia in a range of brain pathologies. Despite its extensive use as a target in molecular imaging studies, the exact cellular functions of this protein remain in question. The long-held view that TSPO plays a fundamental role in the translocation of cholesterol through the mitochondrial membranes, and thus, steroidogenesis, has been disputed by several groups with the advent of TSPO knockout mouse models. Instead, much evidence is emerging that TSPO plays a fundamental role in cellular bioenergetics and associated mitochondrial functions, also part of a greater role in the innate immune processes of microglia. In this review, we examine the more direct experimental literature surrounding the immunomodulatory effects of TSPO. We also review studies which highlight a more central role for TSPO in mitochondrial processes, from energy metabolism, to the propagation of inflammatory responses through reactive oxygen species (ROS) modulation. In this way, we highlight a paradigm shift in approaches to TSPO functioning.

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“…In addition, the GABA AR antagonist bicuculline prevents the neuroprotective effect of propofol via GABA AR function, suggesting the importance of GABA receptor activity in modulating excitotoxicity [ 157 ]. Endogenous neurosteroids can also induce neuroprotection by upregulating GAD67 enzyme level [ 160 ] or GABA AR function [ 161 ]. Thus, even if transient changes in GABAergic synaptic transmission after SCI might not be immediately translated into neuroprotection, other GABAergic targets are available to perform this role.…”

Section: Pharmacological Neuroprotection By Gaba Modulation After Experimental Lesionmentioning

confidence: 99%

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

et al. 2021

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Correct operation of neuronal networks depends on the interplay between synaptic excitation and inhibition processes leading to a dynamic state termed balanced network. In the spinal cord, balanced network activity is fundamental for the expression of locomotor patterns necessary for rhythmic activation of limb extensor and flexor muscles. After spinal cord lesion, paralysis ensues often followed by spasticity. These conditions imply that, below the damaged site, the state of balanced networks has been disrupted and that restoration might be attempted by modulating the excitability of sublesional spinal neurons. Because of the widespread expression of inhibitory GABAergic neurons in the spinal cord, their role in the early and late phases of spinal cord injury deserves full attention. Thus, an early surge in extracellular GABA might be involved in the onset of spinal shock while a relative deficit of GABAergic mechanisms may be a contributor to spasticity. We discuss the role of GABA A receptors at synaptic and extrasynaptic level to modulate network excitability and to offer a pharmacological target for symptom control. In particular, it is proposed that activation of GABA A receptors with synthetic GABA agonists may downregulate motoneuron hyperexcitability (due to enhanced persistent ionic currents) and, therefore, diminish spasticity. This approach might constitute a complementary strategy to regulate network excitability after injury so that reconstruction of damaged spinal networks with new materials or cell transplants might proceed more successfully.

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A novel translocator protein 18 kDa ligand, ZBD‐2, exerts neuroprotective effects against acute spinal cord injury

Cited by 8 publications

References 47 publications

TSPO regulation in reactive gliotic diseases

TSPO regulation in reactive gliotic diseases

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks

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