The impact of postsynaptic density 95 blocking peptide (Tat‐NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate‐induced epileptogenesis

Tse, Karen; Hammond, Dean E.; Simpson, Deborah M.; Beynon, Robert J.; Beamer, Edward; Tymianski, Michael; Salter, Michael W.; Sills, Graeme J.; Thippeswamy, Thimmasettappa

doi:10.1002/jnr.24441

Cited by 11 publications

(9 citation statements)

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“…In addition, a recent study demonstrated that pharmacological inhibition of Fyn decreased Fyn and tau interaction in a mouse model of tauopathy and prevented neurodegeneration resulting in improved learning and memory (Tang et al, 2020 ). Other approaches, such as inducing site-specific tau phosphorylation at Thr205 or blocking PSD-95 using tat-NR2B9c peptide have been reported to dissociate NR2B/PSD-95/tau/Fyn complexes leading to the rescue of neurotoxicity (Ittner et al, 2016 ; Tse et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

Putra

Puttachary

Liu

et al. 2020

Front. Cell. Neurosci.

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Both Fyn and tau have been associated with neuronal hyperexcitability and neurotoxicity in many tauopathies, including Alzheimer's disease (AD). Individual genetic ablation of fyn or tau appears to be protective against aberrant excitatory neuronal activities in AD and epilepsy models. It is, however, still unknown whether ablation of both Fyn and tau can likely elicit more profound anti-seizure and neuroprotective effects. Here, we show the effects of genetic deletion of Fyn and/or tau on seizure severity in response to pentylenetetrazole (PTZ)-induced seizure in mouse models and neurobiological changes 24 h post-seizures. We used Fyn KO (fyn−/−), tau KO (tau−/−), double knockout (DKO) (fyn−/−/tau−/−), and wild-type (WT) mice of the same genetic background. Both tau KO and DKO showed a significant increase in latency to convulsive seizures and significantly decreased the severity of seizures post-PTZ. Although Fyn KO did not differ significantly from WT, in response to PTZ, Fyn KO still had 36 ± 8% seizure reduction and a 30% increase in seizure latency compared to WT. Surprisingly, in contrast to WT, Fyn KO mice showed higher mortality in <20 min of seizure induction; these mice had severe hydrocephalous. None of the tau−/− and DKO died during the study. In response to PTZ, all KO groups showed a significant reduction in neurodegeneration and gliosis, in contrast to WT, which showed increased neurodegeneration [especially, parvalbumin (PV)-GABAergic interneurons] and gliosis. DKO mice had the most reduced gliosis. Immunohistochemically, phospho-tau (AT8, pS199/S202), Fyn expression, as well as Fyn-tau interaction as measured by PLA increased in WT post-PTZ. Moreover, hippocampal Western blots revealed increased levels of AT8, tyrosine phospho-tau (pY18), and phosphorylated Src tyrosine family kinases (pSFK) in PTZ-treated WT, but not in KO, compared to respective controls. Furthermore, PV interneurons were protected from PTZ-induced seizure effects in all KO mice. The levels of inwardly rectifying potassium (Kir 4.1) channels were also downregulated in astrocytes in the WT post-PTZ, while its levels did not change in KO groups. Overall, our results demonstrated the role of Fyn and tau in seizures and their impact on the mediators of early epileptogenesis in PTZ model.

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Section: Discussionmentioning

confidence: 99%

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

Putra

Puttachary

Liu

et al. 2020

Front. Cell. Neurosci.

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“…The hippocampal lysates were processed for proteome analysis, as described previously ( 33 ). For digestion, 15 μl (~100 μg) of homogenate was diluted to 160 μl of ammonium bicarbonate in LoBind tubes.…”

Section: Methodsmentioning

confidence: 99%

“…All peptide separations were carried out using a nanoAcquity UPLC™ system (Waters MS Technologies, Manchester, UK), as previously described ( 33 ). For each analysis, 1 μl of sample digest was loaded onto a trapping column (C 18 , 180 μm × 20 mm, Waters), using partial loop injections for 3 min at 5 μl/min with an aqueous solution containing 0.1% (v/v) TFA and 2% (v/v) acetonitrile.…”

Section: Methodsmentioning

confidence: 99%

The Impacts of Surgery and Intracerebral Electrodes in C57BL/6J Mouse Kainate Model of Epileptogenesis: Seizure Threshold, Proteomics, and Cytokine Profiles

et al. 2021

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Intracranial electroencephalography (EEG) is commonly used to study epileptogenesis and epilepsy in experimental models. Chronic gliosis and neurodegeneration at the injury site are known to be associated with surgically implanted electrodes in both humans and experimental models. Currently, however, there are no reports on the impact of intracerebral electrodes on proteins in the hippocampus and proinflammatory cytokines in the cerebral cortex and plasma in experimental models. We used an unbiased, label-free proteomics approach to identify the altered proteins in the hippocampus, and multiplex assay for cytokines in the cerebral cortex and plasma of C57BL/6J mice following bilateral surgical implantation of electrodes into the cerebral hemispheres. Seven days following surgery, a repeated low dose kainate (KA) regimen was followed to induce status epilepticus (SE). Surgical implantation of electrodes reduced the amount of KA necessary to induce SE by 50%, compared with mice without surgery. Tissues were harvested 7 days post-SE (i.e., 14 days post-surgery) and compared with vehicle-treated mice. Proteomic profiling showed more proteins (103, 6.8% of all proteins identified) with significantly changed expression (p < 0.01) driven by surgery than by KA treatment itself without surgery (27, 1.8% of all proteins identified). Further, electrode implantation approximately doubled the number of KA-induced changes in protein expression (55, 3.6% of all identified proteins). Further analysis revealed that intracerebral electrodes and KA altered the expression of proteins associated with epileptogenesis such as inflammation (C1q system), neurodegeneration (cystatin-C, galectin-1, cathepsin B, heat-shock protein 25), blood–brain barrier dysfunction (fibrinogen-α, serum albumin, α2 macroglobulin), and gliosis (vimentin, GFAP, filamin-A). The multiplex assay revealed a significant increase in key cytokines such as TNFα, IL-1β, IL-4, IL-5, IL-6, IL-10, IL12p70, IFN-γ, and KC/GRO in the cerebral cortex and some in the plasma in the surgery group. Overall, these findings demonstrate that surgical implantation of depth electrodes alters some of the molecules that may have a role in epileptogenesis in experimental models.

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“…With the kainic acid-induced status epilepticus, 1400 W, by decreasing the epileptiform spike rate in the first three days of after status epilepticus and can potentially modify the development of epileptogenesis and reduce the severity of chronic epilepsy [ 134 ]. Thus, 1400W is also revealed to modulate proteins involving neuroinflammatory responses such as heat shock protein beta-1, glial fibrillary acidic protein, and CD44 antigen in kainic acid-induced status epilepticus [ 178 ]. No clinical trial was found regarding “brain disease and 1400 W” from ClinicalTrials.gov.…”

Section: The Potentials Of Antioxidants In Status Epilepticusmentioning

confidence: 99%

Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial?

et al. 2020

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Epilepsy is a common neurological disorder which affects patients physically and mentally and causes a real burden for the patient, family and society both medically and economically. Currently, more than one-third of epilepsy patients are still under unsatisfied control, even with new anticonvulsants. Other measures may be added to those with drug-resistant epilepsy. Excessive neuronal synchronization is the hallmark of epileptic activity and prolonged epileptic discharges such as in status epilepticus can lead to various cellular events and result in neuronal damage or death. Unbalanced oxidative status is one of the early cellular events and a critical factor to determine the fate of neurons in epilepsy. To counteract excessive oxidative damage through exogenous antioxidant supplements or induction of endogenous antioxidative capability may be a reasonable approach for current anticonvulsant therapy. In this article, we will introduce the critical roles of oxidative stress and further discuss the potential use of antioxidants in this devastating disease.

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The impact of postsynaptic density 95 blocking peptide (Tat‐NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate‐induced epileptogenesis

Cited by 11 publications

References 76 publications

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

Fyn-tau Ablation Modifies PTZ-Induced Seizures and Post-seizure Hallmarks of Early Epileptogenesis

The Impacts of Surgery and Intracerebral Electrodes in C57BL/6J Mouse Kainate Model of Epileptogenesis: Seizure Threshold, Proteomics, and Cytokine Profiles

Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial?

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