| Popis: |
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the Central Nervous System (CNS) featuring severe neuronal degenerative processes. Emerging findings indicate that several injurious molecular and cellular cascades are contributing to neurodegeneration. Among them, CNS acidosis has been recently demonstrated to have a detrimental role in Experimental Autoimmune Encephalomyelitis (EAE). Good candidates to trigger acidosis-mediated neurodegeneration are represented by Acid Sensing Ion Channels (ASICs) which are H+-gated cation channels of the CNS. We measured CNS acidosis in EAE mice by a non-invasive magnetic resonance spectroscopy (MRS), establishing the presence of a substantial extracellular acidification in the Cerebellum (CB). We next examined the ability of Diminazene Aceturate (DA), a new specific ASICs inhibitor, to promote neuroprotective effects in chronic EAE mice. Behavioral and histological evaluations indicated that DA significantly improved walking performances in EAE mice, ameliorated their neurological deficits, as well as, reduced myelin and axonal loss in both CB and Spinal Cord. Additionally, we model in vitro the harmful electrophysiological alterations elicited by acidosis using primary neuronal cultures coupled with Micro Electrode Array (MEA) devices. While an acute acidic treatment caused a rapid and transient reduction of firing activity, long term acidosis caused the chronic impairment of synchronized neuronal electrophysiological activity, and a significant loss of pre-synaptic boutons. DA efficiently compensated the loss of firing activity derived from acute acidosis, as well as protected neurons from injurious effects elicited by chronic acidosis. In conclusion our data suggest that ASICs activation is involved in mediating neuronal derangement during acute neuroinflammation and that the early intervention with specific ASICs antagonists may attenuate these detrimental effects. |
