Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy.
Neuroimmunolgy Unit, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Italy; Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, Milan, Italy.
Brain Behav Immun. 2015 Mar;45:263-76. doi: 10.1016/j.bbi.2014.12.003. Epub 2014 Dec 12.
Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection.
局部酸中毒与神经炎症有关，并可能对多种神经紊乱产生重大影响，包括多发性硬化症、脑缺血、脊髓损伤和癫痫。尽管局部酸中毒与许多病理功能有关，但对病理性酸中毒对神经网络活动和突触结构特性的调节作用知之甚少。使用非侵入性磁共振波谱成像，我们在实验性自身免疫性脑脊髓炎（EAE）受影响的小鼠中枢神经系统中发现了持续的细胞外酸中毒。通过皮质神经元的多单位记录，我们确定酸中毒会影响网络活动，缩小放电和爆发行为以及幅度。此外，持续的酸中毒会减少突触前终端的数量，而不会影响突触后区。在酸中毒期间应用二脒基二嗪乙酸盐（DA）可显著逆转神经元放电和爆发的丧失以及突触前终端的减少。最后，体内 DA 给药可改善 EAE 小鼠的临床病程，减少脱髓鞘和轴突损伤。DA 已知可阻断酸感应离子通道（ASICs），这是质子门控、电压不敏感、Na+可渗透的通道，主要由周围和中枢神经系统神经元表达。我们的数据表明，酸中毒期间 ASICs 的激活调节网络电活动并加重 EAE 小鼠的神经退行性变。因此，在神经炎症性疾病中对 ASICs 的药理学调节可能代表未来神经保护治疗的一种新的有前途的策略。
