Hotchkiss Brain Institute, University of Calgary, Alberta, T2N 4N1, Canada.
Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Alberta, T2N 1N4, Canada.
Theranostics. 2024 May 19;14(8):3150-3177. doi: 10.7150/thno.96270. eCollection 2024.
Current pharmacological therapeutic approaches targeting chronic inflammation exhibit transient efficacy, often with adverse effects, limiting their widespread use - especially in the context of neuroinflammation. Effective interventions require the consideration of homeostatic function, pathway dysregulation, and pleiotropic effects when evaluating therapeutic targets. Signalling molecules have multiple functions dependent on the immune context, and this complexity results in therapeutics targeting a single signalling molecule often failing in clinical translation. Additionally, the administration of non-physiologic levels of neurotrophic or anti-inflammatory factors can alter endogenous signalling, resulting in unanticipated effects. Exacerbating these challenges, the central nervous system (CNS) is isolated by the blood brain barrier (BBB), restricting the infiltration of many pharmaceutical compounds into the brain tissue. Consequently, there has been marked interest in therapeutic techniques capable of modulating the immune response in a pleiotropic manner; ultrasound remains on this frontier. While ultrasound has been used therapeutically in peripheral tissues - accelerating healing in wounds, bone fractures, and reducing inflammation - it is only recently that it has been applied to the CNS. The transcranial application of low intensity pulsed ultrasound (LIPUS) has successfully mitigated neuroinflammation , in models of neurodegenerative disease across a broad spectrum of ultrasound parameters. To date, the underlying biological effects and signalling pathways modulated by ultrasound are poorly understood, with a diverse array of reported molecules implicated. The distributed nature of the beneficial response to LIPUS implies the involvement of an, as yet, undetermined upstream signalling pathway, homologous to the protective effect of febrile range hyperthermia in chronic inflammation. As such, we review the heat shock response (HSR), a protective signalling pathway activated by thermal and mechanical stress, as the possible upstream regulator of the anti-inflammatory effects of ultrasound.
当前针对慢性炎症的药物治疗方法显示出短暂的疗效，通常伴有不良反应，这限制了它们的广泛应用 - 特别是在神经炎症的情况下。在评估治疗靶点时，有效的干预措施需要考虑体内平衡功能、途径失调和多效性效应。信号分子的功能取决于免疫环境的多个功能，这种复杂性导致针对单个信号分子的治疗方法在临床转化中经常失败。此外，给予非生理水平的神经营养或抗炎因子会改变内源性信号，导致意外的影响。加剧这些挑战的是，中枢神经系统（CNS）被血脑屏障（BBB）隔离，限制了许多药物化合物渗透到脑组织中。因此，人们对能够以多效方式调节免疫反应的治疗技术产生了浓厚的兴趣；超声仍然处于这一前沿。虽然超声已经在周围组织中被用于治疗 - 加速伤口、骨折的愈合并减少炎症 - 但直到最近才被应用于中枢神经系统。低强度脉冲超声（LIPUS）的经颅应用成功减轻了神经炎症 ，在多种超声参数的神经退行性疾病模型中都有效果。迄今为止，超声调制的潜在生物学效应和信号通路知之甚少，有多种报道的分子与之相关。LIPUS 有益反应的分布式性质意味着涉及到尚未确定的上游信号通路，类似于慢性炎症中发热范围高热的保护作用。因此，我们回顾了热休克反应（HSR），这是一种由热和机械应激激活的保护信号通路，作为超声抗炎作用的可能上游调节剂。
