Neuronal activity‐dependent increase of net matrix metalloproteinase activity is associated with MMP‐9 neurotoxicity after kainate

Abstract

Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) are emerging as important modulators of brain physiopathology. Dramatic changes in the expression of MMPs and TIMPs occur during excitotoxic/neuroinflammatory processes. However, only the measurement of net protease activity is relevant physiologically, and the functional consequences of MMP/TIMP ratio modifications in the brain remain elusive. In order to assess MMP activity and effects in brain tissue, we combined in vivo and organotypic culture models of kainate (KA)-induced excitotoxicity to provoke selective neuronal death and neuroinflammation in the hippocampus. Using in situ zymography, we show that KA-induced excitotoxic seizures in rats increase net MMP activity in hippocampal neurons 8 h after seizures, before their death, and that this increase is neuronal activity-dependent. Three days after KA, proteolytic activity increases in blood vessels and reactive glial cells of vulnerable areas, in relation with neuroinflammation. At 7 and 15 days, proteolysis remains high in blood vessels whereas it is reduced in glia. In organotypic hippocampal cultures, which lack blood cell-mediated inflammation and extrinsic connections, a broad-spectrum inhibitor of MMPs (MMPI), but also a selective MMP-9 inhibitor, protect hippocampal neurons against KA-induced excitotoxicity. Moreover, recombinant MMP-9, but not MMP-2, induces selective pyramidal cell death in these cultures and KA-induced neuronal activity exacerbates the neuronal death promoting effects of MMP-9. These data strongly implicate MMPs, and MMP-9 in particular, in both excitotoxic neuronal damage and subsequent neuroinflammatory processes, and suggest that selective MMPIs could be therapeutically relevant in related neurological disorders.

Original article. Patterns of microglial innate immune responses elicited by amyloid β1–42and lipopolysaccharide: the similarities of the differences

“…This is consistent with many other reports regarding proinflammatory and neurotoxic properties of fAβ [11,30,44]. Furthermore, increased expression of MMP-9 by nfAβ , as observed herein, may amplify microglial toxicity through its direct neurotoxic effect and ability to facilitate maturation of pro-IL-1β [45,46].…”

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

“…Recent studies have linked MMPs to various pathologic conditions in the central nervous system, including ischemia, multiple sclerosis, Parkinson's disease, malignant glioma, Alzheimer's disease, and epilepsy. Interestingly, some evidence suggests that, in addition to its known extracellular role in macromolecule degradation, MMP may mediate apoptotic and/or necrotic cell death (Jourquin et al, 2003;Kim et al, 2009) and synaptic plasticity (Tian et al, 2007;Wilczynski et al, 2008;Takács et al, 2010). The gelatinases MMP-2 and MMP-9 are initially expressed as inactive proenzymes that are cleaved to their active forms after they are released from cells (Van den Steen et al, 2002), allowing these proteases to regulate the levels of extracellular substrates.…”

“…After seizure, MMP-9 mRNA is transported to dendrites and synapses in the hippocampal DG of kainic acid-treated rats . Jourquin et al (2003) used organotypic cultures to demonstrate increased release and activity of MMP-9 after stimulation with neurotoxic kainate and reduced neuronal cell death following MMP-9 inhibition. Although MMP-9 is expressed in response to neural activity in some models of epileptogenesis (Wilczynski et al, 2008;Kim et al, 2009;Takács et al, 2010), the pathophysiologic and etiologic roles of this metalloproteinase, including potential molecular targets, during kindling seizure development have not been elucidated.…”

Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction

“…The most obvious example is excitotoxicity, which occurs if glutamate receptor activation becomes excessive or prolonged, leading to the point where the target neurons become damaged and eventually die, for example, in the CA1 and CA3 hippocampal subfields after the kainate 25,26 and indeed using kainate treatment of the organotypic hippocampal cultures Jourquin et al 15 showed that MMP-9 is directly involved in the excitotoxic neuronal loss. Furthermore, overexpression of TIMP-1 in such cultures showed neuroprotective effect after excessive glutamate stimulation.…”

“…[6][7][8][9] MMP-9 is expressed ubiquitously, albeit at low levels, in various mammalian organs and tissues, including the adult brain 10,11 where it is produced mainly by neurons, and, to some extent, by glia. [12][13][14][15] Recently, we studied a subcellular localization of MMP-9 in the rat hippocampus, using highresolution morphological as well as biochemical approaches. 16 At the ultrastructural level, MMP-9 was found to be present in a subset of dendritic spines bearing asymmetric (e.g.…”