Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

被引:22
作者
Chia, Jasmine Siew Min [1 ,2 ]
Izham, Noor Aishah Mohammed [1 ]
Farouk, Ahmad Akira Omar [1 ]
Sulaiman, Mohd Roslan [1 ]
Mustafa, Sanam [3 ]
Hutchinson, Mark R. [4 ]
Perimal, Enoch Kumar [1 ,4 ]
机构
[1] Univ Putra Malaysia, Fac Med & Hlth Sci, Dept Biomed Sci, Serdang, Malaysia
[2] Univ Kebangsaan Malaysia, Fac Hlth Sci, Ctr Community Hlth Studies, Kuala Lumpur, Malaysia
[3] Univ Adelaide, Fac Hlth & Med Sci, Adelaide, SA, Australia
[4] Univ Adelaide, Australian Res Council Ctr Excellence Nanoscale B, Adelaide, SA, Australia
关键词
zerumbone; neuropathic pain; alpha(2A)-adrenoceptor; TRPV1; NMDA NR2B; allodynia and hyperalgesia; PRIMARY SENSORY NEURONS; DORSAL-HORN NEURONS; LOCUS-COERULEUS; THERMAL HYPERALGESIA; MOUSE MODEL; CAPSAICIN RECEPTOR; BEHAVIORAL SENSITIZATION; ANTINOCICEPTIVE ACTIVITY; DIFFERENTIATED SH-SY5Y; NORADRENERGIC NEURONS;
D O I
10.3389/fphar.2020.00092
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Zerumbone has shown great potential in various pathophysiological models of diseases, particularly in neuropathic pain conditions. Further understanding the mechanisms of action is important to develop zerumbone as a potential anti-nociceptive agent. Numerous receptors and pathways function to inhibit and modulate transmission of pain signals. Previously, we demonstrated involvement of the serotonergic system in zerumbone's anti-neuropathic effects. The present study was conducted to determine zerumbone's modulatory potential involving noradrenergic, transient receptor potential vanilloid type 1 (TRPV1) and N-methyl-D-aspartate (NMDA) receptors in chronic constriction injury (CCI)-induced in vitro and lipopolysaccharide (LPS)-induced SH-SY5Y in vitro neuroinflammatory models. von Frey filament and Hargreaves plantar tests were used to assess allodynia and hyperalgesia in the chronic constriction injury-induced neuropathic pain mouse model. Involvement of specific adrenoceptors were investigated using antagonists- prazosin (alpha(1)-adrenoceptor antagonist), idazoxan (alpha(2)-adrenoceptor antagonist), metoprolol (beta(1)-adrenoceptor antagonist), ICI 118,551 (beta(2)-adrenoceptor antagonist), and SR 59230 A (beta(3)-adrenoceptor antagonist), co-administered with zerumbone (10 mg/kg). Involvement of excitatory receptors; TRPV and NMDA were conducted using antagonists capsazepine (TRPV1 antagonist) and memantine (NMDA antagonist). Western blot was conducted to investigate the effect of zerumbone on the expression of alpha(2A)-adrenoceptor, TRPV1 and NMDA NR2B receptors in CCI-induced whole brain samples of mice as well as in LPS-induced SH-SY5Y neuroblastoma cells. Pre-treatment with alpha(1)- and alpha(2)-adrenoceptor antagonists significantly attenuated both anti-allodynic and anti-hyperalgesic effects of zerumbone. For beta-adrenoceptors, only beta(2)-adrenoceptor antagonist significantly reversed the anti-allodynic and anti-hyperalgesic effects of zerumbone. beta(1)-adrenoceptor antagonist only reversed the anti-allodynic effect of zerumbone. The anti-allodynic and anti-hyperalgesic effects of zerumbone were both absent when TRPV1 and NMDA receptors were antagonized in both nociceptive assays. Zerumbone treatment markedly decreased the expression of alpha(2A)-adrenoceptor, while an up-regulation was observed of NMDA NR2B receptors. Expression of TRPV1 receptors however did not significantly change. The in vitro study, representing a peripheral model, demonstrated the reduction of both NMDA NR2B and TRPV1 receptors while significantly increasing alpha(2A)-adrenoceptor expression in contrast to the brain samples. Our current findings suggest that the alpha(1)-, alpha(2)-, beta(1)- and beta(2)-adrenoceptors, TRPV1 and NMDA NR2B are essential for the anti-allodynic and antihyperalgesic effects of zerumbone. Alternatively, we demonstrated the plasticity of these receptors through their response to zerumbone's administration.
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页数:18
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