Department of Pediatrics, Bolu Izzet Baysal State Hospital, Bolu, Turkey.
Department of Pediatrics, Faculty of Medicine, Bolu Abant Izzet Baysal University, Bolu, Turkey.
Chem Biol Interact. 2023 May 1;376:110450. doi: 10.1016/j.cbi.2023.110450. Epub 2023 Mar 15.
Excitotoxicity and neuroinflammation are key contributors to perinatal brain injuries. Capsaicin, an active ingredient of chili peppers, is a potent exogenous agonist for transient receptor potential vanilloid 1 receptors. Although the neuroprotective and anti-inflammatory effects of capsaicin are well-documented, its effects on excitotoxic-induced neonatal brain injury and neuroinflammation have not previously been investigated. The aim of this study was to investigate the effects of capsaicin on brain damage, brain mast cells, and inflammatory mediators in a model of ibotenate-induced excitotoxic brain injury in neonatal rats. P5 rat-pups were intraperitoneally injected with vehicle, 0.2-, 1-, and 5-mg/kg doses of capsaicin, or the NMDA (N-methyl-d-aspartate) receptor antagonist MK-801 (dizocilpine), 30 min before intracerebral injection of 10 μg ibotenate. The naive-control group received no substance administration. The rat pups were sacrificed one or five days after ibotenate injection. Levels of activin A and interleukin (IL)-1β, IL-6, and IL-10 in brain tissue were measured using the enzyme-linked immunosorbent assay method. Cortex and white matter thicknesses, white matter lesion size, and mast cells were evaluated in brain sections stained with cresyl-violet or toluidine-blue. Capsaicin improved ibotenate-induced white matter lesions and cerebral white and gray matter thicknesses in a dose-dependent manner. In addition, it suppressed the degranulation and increased number of brain mast cells induced by ibotenate. Capsaicin also reduced the excitotoxic-induced production of neuronal survival factor activin A and of the pro-inflammatory cytokines IL-1β, and IL-6 in brain tissue. However, IL-10 levels were not altered by the treatments. MK-801, as a positive control, reversed all these ibotenate-induced changes, further confirming the success of the model. Our findings provide, for the first time, evidence for the therapeutic effects of capsaicin against excitotoxic-induced neonatal brain injury and brain mast cell-mediated neuroinflammation. Capsaicin may therefore be a promising candidate in the prevention and/or reduction of neonatal brain damage.
兴奋性毒性和神经炎症是围产期脑损伤的主要原因。辣椒素是辣椒的一种活性成分，是瞬时受体电位香草素 1 受体的有效外源性激动剂。尽管辣椒素的神经保护和抗炎作用已有充分的记录，但它对兴奋性毒性诱导的新生儿脑损伤和神经炎症的影响尚未被研究过。本研究旨在探讨辣椒素对新生大鼠脑内兴奋性毒素诱导脑损伤模型中脑损伤、脑肥大细胞和炎症介质的影响。P5 日龄大鼠腹腔内注射载体、0.2、1 和 5mg/kg 剂量的辣椒素或 NMDA（N-甲基-D-天冬氨酸）受体拮抗剂 MK-801（地卓西平），30min 后向脑内注射 10μg 海人酸。幼稚对照组不给予任何物质处理。大鼠在海人酸注射后 1 或 5 天处死。采用酶联免疫吸附试验法检测脑组织中激活素 A 和白细胞介素（IL）-1β、IL-6 和 IL-10 的水平。用甲苯胺蓝或甲苯胺蓝染色的脑切片评估皮质和白质厚度、白质病变大小和肥大细胞。辣椒素以剂量依赖的方式改善海人酸诱导的白质病变和大脑白质和灰质厚度。此外，它抑制了海人酸诱导的脑肥大细胞脱颗粒和数量增加。辣椒素还降低了兴奋性毒性诱导的神经元存活因子激活素 A 和脑组织中促炎细胞因子 IL-1β和 IL-6 的产生。然而，治疗并未改变 IL-10 水平。MK-801 作为阳性对照，逆转了所有这些海人酸诱导的变化，进一步证实了该模型的成功。我们的研究结果首次提供了辣椒素治疗兴奋性毒性诱导的新生儿脑损伤和脑肥大细胞介导的神经炎症的治疗效果的证据。因此，辣椒素可能是预防和/或减少新生儿脑损伤的有前途的候选药物。
