MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling

Phạm, Thuỳ Linh; Noh, Chan; Neupane, Chiranjivi; Sharma, Ramesh; Shin, Hyun Jin; Park, Ki Duk; Lee, C. Justin; Kim, Hyun Woo; Lee, So Yeong; Park, Jin Bong

doi:10.1016/j.jpain.2022.07.010

Cited by 11 publications

(6 citation statements)

References 62 publications

(83 reference statements)

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“…NMDAR phosphorylation reduces the voltage-dependent Mg 2+ block of the channels ( Chen and Huang, 1992 ), leading to, as recently shown ( Pham et al, 2022 ), an increase in I ifenprodil . The lack of increase in I ifenprodil in this study suggests that NR2B phosphorylation is not a likely mechanism contributing to changes in NMDAR function reported in DOCA-salt rats.…”

Section: Discussionmentioning

confidence: 78%

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus

Shin,

Sharma,

Neupane

et al. 2024

eNeuro

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NMDA receptors (NMDARs) modulate glutamatergic excitatory tone in the brain via two complementary modalities: a phasic excitatory postsynaptic current and a tonic extrasynaptic modality. Here, we demonstrated that the tonic extrasynaptic NMDAR- current (INMDA) mediated by NR2A-containing NMDARs is an efficient biosensor detecting the altered ambient glutamate level in the supraoptic nucleus (SON). INMDAof magnocellular neurosecretory cells (MNCs) measured by nonselective NMDARs antagonist, AP5, at holding potential (Vholding) -70 mV in low concentration of ECF Mg2+([Mg2+]o) was transiently but significantly increased 1-week post induction of a DOCA (deoxycorticosterone) -salt hypertensive model rat. The INMDAuncovered by AP5 was compatible with that induced by a NR2A-selective antagonist, PEAQX (IPEAQX) in both DOCA-H2O (animals receive normal water after DOCA) and DOCA-salt (animals receive a mixture of 0.8% NaCl and 0.2% KCl in water after DOCA) groups. In agreement, NR2B antagonist, ifenprodil, or NR2C/D antagonist, PPDA, did not affect the holding current (Iholding) at Vholding-70 mV. Increased ambient glutamate by exogenous glutamate (10 μM) or glutamate transporter / excitatory amino acid transporters (EAATs) antagonist (TBOA, 50 μM) abolished the IPEAQXdifference between DOCA-H2O and DOCA-salt group, suggesting that attenuated EAATs activity increased ambient glutamate concentration, leading to the larger IPEAQXin DOCA-salt rats. In contrast, only ifenprodil but not PEAQX and PPDA uncovered INMDAat Vholding+40 mV under 1.2 mM [Mg2+]ocondition. Iifenprodilwas not different in DOCA-H2O and DOCA-salt groups. Finally, NR2A, NR2B, and NR2D protein expression were not different in the SON of the two groups. Taken together, NR2A-containing NMDARs efficiently detected the increased ambient glutamate concentration in the SON of DOCA-salt hypertensive rats due to attenuated EAATs activity.Significance StatementThe NMDAR-mediated excitatory tone between cells is transmitted via a phasic activation of synaptic NMDARs (EPSCs) and tonic activation of extrasynaptic NMDARs (INMDA) in the brain. The activation of NMDARs depends on the glutamate concentration, NMDAR subunit composition, and their subcellular localization, as well as the membrane potential. Therefore, the mechanism of NMDAR-mediated excitatory tone varies in different pathophysiological conditions. Our results show that the INMDAin non-depolarized and depolarized neurons is dominantly mediated by NR2A- and NR2B-containing NMDARs, respectively, and the former efficiently detects the ambient glutamate concentration in the supraoptic magnocellular neuroendocrine cells of normal and hypertensive rats. This study shows that NR2A-containing NMDARs could be a biosensor detecting ambient glutamate concentration in the brain.

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Section: Discussionmentioning

confidence: 78%

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus

Shin,

Sharma,

Neupane

et al. 2024

eNeuro

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“…However, BDNF knockout specimens exhibited a decrease in preganglionic synaptic innervation density to sympathetic neurons, suggesting that BDNF has the ability to increase synaptic density [22]. In addition, with activation of TrkB receptors, there is a downstream activation of various signaling pathway cascades, including the MEK/mitogen-activated protein kinase (MAPK) pathway [73], phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) [74], PI3K/Akt/mammalian target of rapamycin (mTOR) pathway [75], and nuclear factor kappaB (NF-κB) signaling pathways [76]. Each of these processes contributes to the induction and maintenance of CS in different parts of nociceptive pathways by facilitating LTP.…”

Section: The Role Of Bdnf In Central Sensitizationmentioning

confidence: 99%

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation

Xiong,

Hendrix,

Schabrun

et al. 2024

Biomolecules

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Chronic pain is sustained, in part, through the intricate process of central sensitization (CS), marked by maladaptive neuroplasticity and neuronal hyperexcitability within central pain pathways. Accumulating evidence suggests that CS is also driven by neuroinflammation in the peripheral and central nervous system. In any chronic disease, the search for perpetuating factors is crucial in identifying therapeutic targets and developing primary preventive strategies. The brain-derived neurotrophic factor (BDNF) emerges as a critical regulator of synaptic plasticity, serving as both a neurotransmitter and neuromodulator. Mounting evidence supports BDNF’s pro-nociceptive role, spanning from its pain-sensitizing capacity across multiple levels of nociceptive pathways to its intricate involvement in CS and neuroinflammation. Moreover, consistently elevated BDNF levels are observed in various chronic pain disorders. To comprehensively understand the profound impact of BDNF in chronic pain, we delve into its key characteristics, focusing on its role in underlying molecular mechanisms contributing to chronic pain. Additionally, we also explore the potential utility of BDNF as an objective biomarker for chronic pain. This discussion encompasses emerging therapeutic approaches aimed at modulating BDNF expression, offering insights into addressing the intricate complexities of chronic pain.

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“…With activation of TrkB receptors, there is a downstream activation of different signaling pathways. For example, nuclear factor kappaB (NF-κB) and the mitogen-activated protein kinases (MAPK), that include the p38, Jun N-terminal kinase (JNK), and extracellular signal-regulated protein kinase (ERK) signaling pathways are activated (Cappoli et al, 2020;Liu et al, 2007;Obata & Noguchi, 2004;Pha . m et al, 2022;Santana-Martínez et al, 2018).…”

Section: Spinal Dorsal Horn Dorsal Root Ganglia and Microglia Mediate...mentioning

confidence: 99%

“…With activation of TrkB receptors, there is a downstream activation of different signaling pathways. For example, nuclear factor kappaB (NF‐ κB) and the mitogen‐activated protein kinases (MAPK), that include the p38, Jun N‐terminal kinase (JNK), and extracellular signal‐regulated protein kinase (ERK) signaling pathways are activated (Cappoli et al., 2020; Liu et al., 2007; Obata & Noguchi, 2004; Pezet & McMahon, 2006; Phạm et al., 2022; Santana‐Martínez et al., 2018). Obata and Noguchi (2004) have also demonstrated that MAPK signaling pathways, specifically ERK and p38 are involved in heat hyperalgesia and nerve injury induced neuroinflammation and neuropathic pain.…”

Section: Bdnf Related Mechanism Of Action In Npmentioning

confidence: 99%

BDNF as a biomarker for neuropathic pain: Consideration of mechanisms of action and associated measurement challenges

Thakkar

Acevedo

2023

Brain and Behavior

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Introduction:The primary objective of this paper is to (1) provide a summary of human studies that have used brain derived neurotrophic factor (BDNF) as a biomarker, (2) review animal studies that help to elucidate the mechanistic involvement of BDNF in the development and maintenance of neuropathic pain (NP), and (3) provide a critique of the existing measurement techniques to highlight the limitations of the methods utilized to quantify BDNF in different biofluids in the blood (i.e., serum and plasma) with the intention of presenting a case for the most reliable and valid technique. Lastly, this review also explores potential moderators that can influence the measurement of BDNF and provides recommendations to standardize its quantification to reduce the inconsistencies across studies. Methods:In this manuscript we examined the literature on BDNF, focusing on its role as a biomarker, its mechanism of action in NP, and critically analyzed its measurement in serum and plasma to identify factors that contribute to the discrepancy in results between plasma and serum BDNF values.Results: A large heterogenous literature was reviewed that detailed BDNF's utility as a potential biomarker in healthy volunteers, patients with chronic pain, and patients with neuropsychiatric disorders but demonstrated inconsistent findings. The literature provides insight into the mechanism of action of BDNF at different levels of the central nervous system using animal studies. We identified multiple factors that influence the measurement of BDNF in serum and plasma and based on current evidence, we recommend assessing serum BDNF levels to quantify peripheral BDNF as they are more stable and sensitive to changes than plasma BDNF. Conclusion:Although mechanistic studies clearly explain the role of BDNF, results from human studies are inconsistent. More studies are needed to evaluate the methodological challenges in using serum BDNF as a biomarker in NP.

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MAO-B Inhibitor, KDS2010, Alleviates Spinal Nerve Ligation-induced Neuropathic Pain in Rats Through Competitively Blocking the BDNF/TrkB/NR2B Signaling

Cited by 11 publications

References 62 publications

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus

The Role of the Brain-Derived Neurotrophic Factor in Chronic Pain: Links to Central Sensitization and Neuroinflammation

BDNF as a biomarker for neuropathic pain: Consideration of mechanisms of action and associated measurement challenges

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