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Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain

Stratton, Harrison J; Boinon, Lisa; Gomez, Kimberly; Martin, Laurent; Duran, Paz; Ran, Dongzhi; Zhou, Yuan; Luo, Shizhen; Perez-Miller, Samantha; Patek, Marcel; Ibrahim, Mohab M; Patwardhan, Amol; Moutal, Aubin; Khanna, Rajesh
Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A-blocked VEGF-A-mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4'-methyl-2'-morpholino-2-(phenylamino)-[4,5'-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A-mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain.
PMID: 36729125
ISSN: 1872-6623
CID: 5434812

Argentatin C Analogues with Potential Antinociceptive Activity and Other Triterpenoid Constituents from the Aerial Parts of Parthenium incanum

Xu, Ya Ming; Wijeratne, E. M.Kithsiri; Calderon-Rivera, Aida; Loya-López, Santiago; Perez-Miller, Samantha; Khanna, Rajesh; Gunatilaka, A. A.Leslie
Four new triterpenes, 25-dehydroxy-25-methoxyargentatin C (1), 20S-hydroxyargentatin C (2), 20S-hydroxyisoargentatin C (3), and 24-epi-argentatin C (4), together with 10 known triterpenes (5-14) were isolated from the aerial parts of Parthenium incanum. The structures of 1-4 were elucidated by detailed analysis of their spectroscopic data, and the known compounds 5-14 were identified by comparison of their spectroscopic data with those reported. Since argentatin C (11) was found to exhibit antinociceptive activity by decreasing the excitability of rat and macaque dorsal root ganglia (DRG) neurons, 11 and its new analogues 1-4 were evaluated for their ability to decrease the excitability of rat DRG neurons. Of the argentatin C analogues tested, 25-dehydroxy-25-methoxyargentatin C (1) and 24-epi-argentatin C (4) decreased neuronal excitability in a manner comparable to 11. Preliminary structure-activity relationships for the action potential-reducing effects of argentatin C (11) and its analogues 1-4, and their predicted binding sites in pain-relevant voltage-gated sodium and calcium channels (VGSCs and VGCCs) in DRG neurons are presented.
ISSN: 2470-1343
CID: 5548732

Glutamatergic and GABAergic neurons in the vLGN mediate the nociceptive effects of green and red light on neuropathic pain

Wu, Xue-Qing; Tan, Bei; Du, Yu; Yang, Lin; Hu, Ting-Ting; Ding, Yi-La; Qiu, Xiao-Yun; Moutal, Aubin; Khanna, Rajesh; Yu, Jie; Chen, Zhong
Phototherapy is an emerging non-pharmacological treatment for depression, circadian rhythm disruptions, and neurodegeneration, as well as pain conditions including migraine and fibromyalgia. However, the mechanism of phototherapy-induced antinociception is not well understood. Here, using fiber photometry recordings of population-level neural activity combined with chemogenetics, we found that phototherapy elicits antinociception via regulation of the ventral lateral geniculate body (vLGN) located in the visual system. Specifically, both green and red lights caused an increase of c-fos in vLGN, with red light increased more. In vLGN, green light causes a large increase in glutamatergic neurons, whereas red light causes a large increase in GABAergic neurons. Green light preconditioning increases the sensitivity of glutamatergic neurons to noxious stimuli in vLGN of PSL mice. Green light produces antinociception by activating glutamatergic neurons in vLGN, and red light promotes nociception by activating GABAergic neurons in vLGN. Together, these results demonstrate that different colors of light exert different pain modulation effects by regulating glutamatergic and GABAergic subpopulations in the vLGN. This may provide potential new therapeutic strategies and new therapeutic targets for the precise clinical treatment of neuropathic pain.
PMID: 37217103
ISSN: 1095-953x
CID: 5503752

The natural product Argentatin C attenuates postoperative pain via inhibition of voltage-gated sodium and T-type voltage-gated calcium channels

Duran, Paz; Loya-López, Santiago; Ran, Dongzhi; Tang, Cheng; Calderon-Rivera, Aida; Gomez, Kimberly; Stratton, Harrison J; Huang, Sun; Xu, Ya-Ming; Wijeratne, E M Kithsiri; Perez-Miller, Samantha; Shan, Zhiming; Cai, Song; Gabrielsen, Anna T; Dorame, Angie; Masterson, Kyleigh A; Alsbiei, Omar; Madura, Cynthia L; Luo, Guoqin; Moutal, Aubin; Streicher, John; Zamponi, Gerald W; Gunatilaka, A A Leslie; Khanna, Rajesh
BACKGROUND AND PURPOSE/OBJECTIVE:Postoperative pain occurs in as many as 70% of the over 230 million surgeries performed annually worldwide. Postoperative pain management still relies on opioids despite their negative consequences, resulting in a public health crisis. Therefore, it is of utmost importance to develop alternative therapies to treat chronic pain. Natural products derived from medicinal plants are potential sources of novel and biologically active compounds for development of safe analgesics. Hence, in this study, we screened a library of natural products to identify small molecules that target the activity of voltage-gated sodium and calcium channels which have important roles in nociceptive sensory processing. EXPERIMENTAL APPROACH/METHODS:Fractions derived from the Native American medicinal plant, Parthenium incanum, were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Further separation of these fractions yielded a cycloartane-type triterpene identified as argentatin C, which was additionally evaluated using whole-cell voltage and current clamp electrophysiology, and behavioral analysis in a mouse model of postsurgical pain. KEY RESULTS/RESULTS:currents as well as excitability in rat and macaque DRG neurons. Consistent with these observations, argentatin C treatment reversed mechanical allodynia in a mouse model of postsurgical pain. CONCLUSIONS & IMPLICATIONS/CONCLUSIONS:These results suggest that the dual effect of argentatin C on voltage-gated sodium and calcium channels supports its potential as a novel treatment for painful conditions.
PMID: 36245395
ISSN: 1476-5381
CID: 5371292

CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease

Brustovetsky, Tatiana; Khanna, Rajesh; Brustovetsky, Nickolay
Mitochondrial bioenergetics and dynamics (alterations in morphology and motility of mitochondria) play critical roles in neuronal reactions to varying energy requirements in health and disease. In Alzheimer's disease (AD), mitochondria undergo excessive fission and become less motile. The mechanisms leading to these alterations are not completely clear. Here, we show that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in AD and that is accompanied by a decreased interaction of CRMP2 with Drp1, Miro 2, and Mitofusin 2, which are proteins involved in regulating mitochondrial morphology and motility. CRMP2 was hyperphosphorylated in postmortem brain tissues of AD patients, in brain lysates, and in cultured cortical neurons from the double transgenic APP/PS1 mice, an AD mouse model. CRMP2 hyperphosphorylation and dissociation from its binding partners correlated with increased Drp1 recruitment to mitochondria, augmented mitochondrial fragmentation, and reduced mitochondrial motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Ser 522 and Thr 509/514, and restored CRMP2's interaction with Miro 2, Drp1, and Mitofusin 2. This was paralleled by decreased Drp1 recruitment to mitochondria, diminished mitochondrial fragmentation, and improved motility of the organelles. Additionally, (S)-LCM-protected cultured cortical AD neurons from cell death. Thus, our data suggest that CRMP2, in a phosphorylation-dependent manner, participates in the regulation of mitochondrial morphology and motility, and modulates neuronal survival in AD.
PMID: 37174687
ISSN: 2073-4409
CID: 5495722

The Emerging Translational Potential of MNK Inhibitors for the Treatment of Chronic Pain [Editorial]

Nelson, Tyler S; Khanna, Rajesh
PMID: 36922084
ISSN: 1873-7544
CID: 5448932

Betulinic acid analogs inhibit N- and T-type voltage-gated calcium channels to attenuate nerve-injury associated neuropathic and formalin models of pain

Calderon-Rivera, Aida; Gomez, Kimberly; Loya-López, Santiago; Wijeratne, E. M.Kithsiri; Stratton, Harrison; Tang, Cheng; Duran, Paz; Masterson, Kyleigh; Alsbiei, Omar; Gunatilaka, A. A.Leslie; Khanna, Rajesh
Over the past three decades, there has been a significant growth in the use of natural products, with approximately 80% of individuals using them for some aspect of primary healthcare. Our laboratories have identified and studied natural compounds with analgesic effects from dry land plants or their associated fungus during the past ten years. Here, we isolated and characterized thirteen betulin analogs and fifteen betulinic acid analogs for their capacity to prevent calcium influx brought on by depolarization in sensory neurons. The in vitro inhibition of voltage-gated calcium channels by the top drugs was then assessed using whole cell patch clamp electrophysiology. In vivo experiments, conducted at two sites, evaluated the best compound in acute and tonic, neuropathic, inflammatory, post-operative and visceral models of pain. We found that the betulinic acid analog 8 inhibited calcium influx in rat dorsal root ganglion neurons by inhibiting N- (CaV2.2) and T- (CaV3) type voltage-gated calcium channels. Moreover, intrathecal delivery of analog 8 had analgesic activity in both spared nerve injury model of neuropathic pain and acute and tonic pain induced by formalin. The results presented herein highlight the potential antinociceptive properties of betulinic acid analog 8 and set the stage for the development of novel non-opioid pain therapeutics based on the triterpenoid scaffold of betulinic acid.
ISSN: 2452-073x
CID: 5408982

Some Like It Hot: Dynamic Control of Cav2.2 Channels By Chili Peppers [Comment]

Duran, Paz; Khanna, Rajesh
PMID: 36632472
ISSN: 2633-8823
CID: 5439512

A new polymodal gating model of the proton-activated chloride channel

Zhao, Piao; Tang, Cheng; Yang, Yuqin; Xiao, Zhen; Perez-Miller, Samantha; Zhang, Heng; Luo, Guoqing; Liu, Hao; Li, Yaqi; Liao, Qingyi; Yang, Fan; Dong, Hao; Khanna, Rajesh; Liu, Zhonghua
ISSN: 1544-9173
CID: 5570002

Neuronal CRMP2 phosphorylation inhibition by the flavonoid, naringenin, contributes to the reversal of spinal sensitization and arthritic pain improvement

Jiang, Yue-Peng; Wang, Song; Lai, Wei-Dong; Wu, Xue-Qing; Jin, Yan; Xu, Zheng-Hao; Moutal, Aubin; Khanna, Rajesh; Park, Ki Duk; Shan, Zhi-Ming; Wen, Cheng-Ping; Yu, Jie
BACKGROUND:Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. METHODS:NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. RESULTS:We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. CONCLUSIONS:Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain.
PMID: 36564853
ISSN: 1478-6362
CID: 5409422