Akt/Aquaporin-4 Signaling Aggravates Neuropathic Pain by Activating Astrocytes after Spinal Nerve Ligation in Rats

Guo, Shiwu; Song, Zhiwen; He, Junsheng; Yin, Gang; Zhu, Jianguo; Liu, Haifeng; Yang, Lei; Ji, Xubiao; Xu, Xu; Liu, Zhiyuan; Wang, Zhibin

doi:10.1016/j.neuroscience.2021.12.015

Cited by 17 publications

(18 citation statements)

References 48 publications

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“…70 Inhibition of AQP4 attenuated the development and maintenance of neuropathic pain by inhibiting glial activation and neuroinflammation in a model of peripheral nerve injury. 71 However, AQP4 knockout reduced compensatory GLT1 upregulation in the setting of peripheral inflammation elicited by intraplanar injection of complete Freund's adjuvant, intensifying central sensitization in this model. 72 There is also upregulation of CX43 after nerve lesions or spinal cord injury with a functional switch from the formation of gap junctions to that of hemichannels.…”

Section: Astrocytic Dysfunction and Central Sensitizationmentioning

confidence: 80%

“…134 As mentioned earlier in this review, the consequences of AQP4 dysfunction in relationship with neuropathic pain are likely to be complex and dependent on the pathologic context. 71,72 NMOSD responds to IL-6 antagonists such as tocilizumab and satralizumab. 135,136 A study showed that tocilizumab reduced chronic pain in patients with refractory NMOSD.…”

Section: Clinical Correlations and Perspectivementioning

confidence: 99%

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What Is the Role of Dorsal Horn Astrocytes in Chronic Pain and Itch?

Benarroch

2022

Neurology

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Astrocytes include different subtypes and exert multiple functions critical for synaptic communication and network activity in the CNS.1 They may ensheath up to million synapses in the human brain2; maintain water, potassium (K+), and glutamate homeostasis after synaptic activity3,4; form a structural barrier around synapses preventing glutamate spillover5; provide lactate as an energy substrate for neurons6; release neurochemical signals that mediate paracrine interactions with neurons and other glial cells7; and guide glymphatic clearance.8 Astrocytes connect with each other through gap junctions. This allows the propagation of calcium (Ca2+) waves within the astrocyte network and spreading of signaling molecules over long distances, thereby regulating neuronal network activity.9

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Section: Astrocytic Dysfunction and Central Sensitizationmentioning

confidence: 80%

Section: Clinical Correlations and Perspectivementioning

confidence: 99%

What Is the Role of Dorsal Horn Astrocytes in Chronic Pain and Itch?

Benarroch

2022

Neurology

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“…The inflammation, edema, and neuronal hyperexcitability are also one of the pathogeneses of neuropathic pain [66,67]. Therefore, there is a strong link between AQP4 and neuropathic pain, which has been demonstrated by many studies [68][69][70]. Since AQP4 is the aquaporin that is most closely associated with neuropathic pain discovered so far, we will discuss several diseases that are accompanied by neuropathic pain in detail (Fig.…”

Section: Aqp4mentioning

confidence: 99%

Aquaporins and Neuropathic Pain

Wang¹,

Xu²,

Xu³

et al. 2023

Front. Biosci. (Landmark Ed)

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Neuropathic pain is a chronic secondary pain condition resulting from lesions or diseases of the peripheral or central nervous system (CNS). Neuropathic pain is closely related to edema, inflammation, increased neuronal excitability, and central sensitization caused by glutamate accumulation. Aquaporins (AQPs), mainly responsible for the transport and clearance of water and solute, play important roles in developing CNS diseases, especially neuropathic pain. This review focuses on the interaction of AQPs with neuropathic pain, and the potential of AQPs, especially aquaporins 4, as therapeutic targets.

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“…Rats with signs of motor dysfunction were excluded from the experiments. Previously, we found that 15µg TGN020 was effective in producing anti-nociception when injected into subarachnoid space in a spinal nerve ligation model [19], and thus, we chose the same dose for evaluating the possible anti-nociceptive effects of intrathecal injection. The dose of TFP was chosen as 15µg and 45µg according to previous research [26].…”

Section: Intrathecal Injectionmentioning

confidence: 99%

“…Astrocytes were involved in central sensitization, especially through glial-neuron interactions in neuropathic pain states [36]. We evaluated whether T13 level SCI affected astrocytes activation, which occur in rats after spinal nerve ligation injury [19].GFAP expressions at the ipsilateral L4/5 segments of SDH after SCI were evaluated by Western blotting. The results suggested that GFAP level was low in the sham group.…”

Section: Aqp4 Blockade Suppressed Astrocytes Activation After Scimentioning

confidence: 99%

Inhibition of Aquaporin-4 and its sub-cellular localization attenuates below-level central neuropathic pain via regulating astrocyte activation in a rat spinal cord injury model

Song

Xue

Guo

et al. 2023

Preprint

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The mechanisms of central neuropathic pain (CNP) caused by spinal cord injury have not been sufficiently studied. We have found that the up-regulation of astrocytic Aquaporin-4 (AQP4) aggravated peripheral neuropathic pain after spinal nerve ligation in rats. Using a T13 spinal cord hemisection model, we showed that spinal AQP4 was markedly up-regulated after SCI and mainly expressed in astrocytes in the spinal dorsal horn (SDH). Inhibition of AQP4 with TGN020 suppressed astrocytes activation, attenuated the development and maintenance of below-level CNP and promoted motor function recovery in vivo. In primary astrocyte cultures, TGN020 also changed cell morphology, diminished cell proliferation and suppressed astrocyte activation. Moreover, T13 spinal cord hemisection induced cell-surface abundance of AQP4 channel and the perivascular localization in the SDH. Targeted inhibition of AQP4 sub-cellular localization with trifluoperazine effectively diminished astrocytes activation in vitro and further ablated astrocytes activation, attenuated the development and maintenance of below-level CNP, and accelerated functional recovery in vivo. Together, these results provide mechanistic insights into the roles of AQP4 in the development and maintenance of below-level CNP. Intervening with AQP4, including targeting AQP4 subcellular localization, might emerges as a promising agent to prevent chronic CNP after SCI.

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Akt/Aquaporin-4 Signaling Aggravates Neuropathic Pain by Activating Astrocytes after Spinal Nerve Ligation in Rats

Cited by 17 publications

References 48 publications

What Is the Role of Dorsal Horn Astrocytes in Chronic Pain and Itch?

What Is the Role of Dorsal Horn Astrocytes in Chronic Pain and Itch?

Aquaporins and Neuropathic Pain

Inhibition of Aquaporin-4 and its sub-cellular localization attenuates below-level central neuropathic pain via regulating astrocyte activation in a rat spinal cord injury model

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