Several cytokines have short-term effects on synaptic transmission and plasticity that are thought to be mediated by the activation of intracellular protein kinases. We have studied the effects of interleukin-6 (IL-6) on the expression of paired pulse facilitation (PPF), posttetanic potentiation (PTP), and long-term potentiation (LTP) in the CA1 region of the hippocampus as well as on the activation of the signal transducer and activator of transcription-3 (STAT3), the mitogen-activated protein kinase ERK (MAPK/ERK), and the stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK). IL-6 induced a marked and dose-dependent decrease in the expression of PTP and LTP that could be counteracted by the simultaneous treatment with the tyrosine kinase inhibitor lavendustin A (LavA) but did not significantly affect PPF. The IL-6-induced inhibition of PTP and LTP was accompanied by a simulation of STAT3 tyrosine phosphorylation and an inhibition of MAPK/ERK dual phosphorylation, in the absence of changes in the state of activation of SAPK/JNK. Both effects of IL-6 on STAT3 and MAPK/ERK activation were effectively counteracted by LavA treatment. The results indicate that tyrosine kinases and MAPK/ERK are involved in hippocampal synaptic plasticity and may represent preferential intracellular targets for the actions of IL-6 in the adult nervous system. Key Words: Long-term potentiation-Posttetanic potentiation-Tyrosine phosphorylation-Mitogenactivated protein kinase -Signal transducer and activator of transcription-3 (STAT3). J. Neurochem. 75, 634 -643 (2000).The molecular mechanisms underlying changes in synaptic efficacy are beginning to be elucidated and, in most cases, involve long-lasting changes at both pre-and postsynaptic levels mediated by the activation of intracellular signal transduction systems as well as by changes in gene expression. There is increasing evidence that protein kinases such as protein kinase C, Ca 2ϩ / calmodulin-dependent protein kinase II, protein kinase A, Src-family protein kinases, and the mitogen-activated protein kinase ERK (MAPK/ERK) are intimately involved in the expression of long-term potentiation (LTP) in the hippocampus (Grant et al
A series of mutant human and yeast copperzinc superoxide dismutases has been prepared, with mutations corresponding to those found in familial amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). These proteins have been characterized with respect to their metal-binding characteristics and their redox reactivities. Replacement of Zn2+ ion in the zinc sites of several of these proteins with either Cu2+ or Co2+ gave metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wild-type proteins, indicating that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc superoxide dismutases were also found to be reduced by ascorbate at significantly greater rate than the wild-type proteins. We conclude that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure. This finding may help to explain what is perhaps the most perplexing question in copper-zinc superoxide dismutase-associated familial ALS-i.e., how such a diverse set of mutations can result in the same gain of function that causes the disease.
Lipid peroxidation has been hypotesized as one of possible factors involved in the pathogenesis of neuronal damage and delayed vasospasm after subarachnoid hemorrhage. In the brain there are anti‐oxidant enzymatic systems which act as scavengers of superoxides and free radicals. In the present study the pattern of enzymatic anti‐oxidant activities (Cu‐Zn and Mn superoxide dismutase, and glutathione peroxidase) was investigated in an experimental model of subarachnoid hemorrhage in the rat in order to verify whether the hemorrhagic insult may be responsible for an impairment of such anti‐oxidant systems. Enzymatic activities were assayed in three different rat brain areas (cerebral cortex, hippocampus and brain stem) of sham‐operated and at 30 min, 1, 6 and 48 h after subarachnoid hemorrhage induction. After the hemorrhage induction the Cu‐Zn superoxide dismutase activity in cerebral cortex was significantly reduced at all the set times (p <.05), while Mn‐superoxide dismutase activity was significantly decreased since 1 h (p <.05) until 48 h (p <.05). Glutathione peroxidase activity was significantly reduced only in the late phase (48 h) of subarachnoid hemorrhage (p <.01). In the hippocampus, all enzymatic activities were significantly reduced in the late phase. In the brain stem Cu‐Zn superoxide dismutase was significantly impaired at 1 and 6 h (p <.05) after subarachnoid hemorrhage induction, while in the late phase (48 h) reached the control value. The mitochondrial Mn‐superoxide dismutase was significantly reduced since 1 h (p <.05) until 48 h (p <.02) after subarachnoid hemorrhage. Glutathione peroxidase activity in this area was impaired at 1, 6 (p <.01) and 48 h (p <.02). These results suggest that subarachnoid hemorrhage causes a significant reduction of anti‐oxidant enzymatic activities in brain compartment: Cu‐Zn and Mn superoxide dismutase, which are specific scavengers of superoxide radicals, show an early decrease, while glutathione peroxidase activity is significantly reduced in a delayed phase.
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