An electrophysiological and proteomic analysis of the effects of the superoxide dismutase mimetic, MnTMPyP, on synaptic signalling post ischemia in isolated rat hippocampal slices.

ABSTRACT: Metabolic stress and the increased production of reactive oxygen species (ROS) are two main contributors to neuronal damage and synaptic plasticity in acute ischemic stroke (AIS). The superoxide scavenger MnTMPyP has been previously reported to have a neuroprotective effect in organotypic hippocampal slices and to modulate synaptic transmission after in vitro hypoxia and oxygen glucose deprivation (OGD). However, the mechanisms involved in the effect of this scavenger remain elusive. In this study we evaluated the concentration dependent effect of MnTMPyP on synaptic transmission during ischemia and post-ischemic synaptic potentiation. We also investigated the complex molecular changes supporting cellular adaptation to metabolic stress and how these are modulated by MnTMPyP. Electrophysiological data showed that MnTMPyP causes a concentration dependent decrease in baseline synaptic transmission and impairment of synaptic potentiation. Proteomic analysis performed on MnTMPyP treated tissue indicated an impairment in vesicular trafficking mechanisms including alteration of Secretory Carrier Membrane Protein 3 (SCAMP3) and RAB proteins and downregulation of mitochondrial-mediated apoptosis. Alterations of vesicular trafficking may lead to reduced probability of neurotransmitter release and AMPA receptor activity, resulting in the observed modulatory effect of MnTMPyP. In ischemia and glucose deprivation, protein enrichment analysis highlighted impairments in cell proliferation and differentiation, such as TGFβ1 and CDKN1B signalling, in addition to downregulation of actin signalling, cell stress and mitochondrial-mediated apoptosis. Taken together our results indicate modulation of neuronal sensitivity to the ischemic insult, and a complex role for MnTMPyP on synaptic transmission and plasticity and provide molecular insights into the mechanisms mediating the effects of MnTMPyP during ischemia

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Caitriona Scaife  

LAB HEAD: John O'Connor

PROVIDER: PXD040890 | Pride | 2023-05-10

REPOSITORIES: Pride