Levetiracetam Protects Against Cognitive Impairment of Subthreshold Convulsant Discharge Model Rats by Activating Protein Kinase C (PKC)-Growth-Associated Protein 43 (GAP-43)-Calmodulin-Dependent Protein Kinase (CaMK) Signal Transduction Pathway

Abstract

Background Subclinical epileptiform discharges (SEDs) are defined as epileptiform electroencephalographic (EEG) discharges without clinical signs of seizure in patients. The subthreshold convulsant discharge (SCD) is a frequently used model for SEDs. This study aimed to investigate the effect of levetiracetam (LEV), an anti-convulsant drug, on cognitive impairment of SCD model rats and to assess the associated mechanisms. Material/Methods A SCD rat model was established. Rats were divided into an SCD group, an SCD+ sodium valproate (VPA) group, and an SCD+ levetiracetam (LEV) group. The Morris water maze was used to evaluate the capacity of positioning navigation and space exploration. The field excitatory post-synaptic potentials (fEPSPs) were evaluated using a bipolar stimulation electrode. NCAM, GAP43, PS95, and CaMK II levels were detected using Western blot and RT-PCR, respectively. PKC activity was examined by a non-radioactive method. Results LEV shortens the latency of platform seeking in SCD rats in positioning navigation. fEPSP slopes were significantly lower in the SCD group, and LEV treatment significantly enhanced the fEPSP slopes compared to the SCD group ( P <0.05). The NCAM and GAP-43 levels were increased and PSD-95 levels were increased in SCD rats ( P <0.05), which were improved by LEV treatment. The PKC activity and CaMK II levels were decreased in SCD rats and LEV treatment significantly enhanced PKC activity and increased CaMK II levels. Conclusions Cognitive impairment in of SCD model rats may be caused by decreased PKC activity, low expression of CaMK II, and inhibition of LTP formation. LEV can improve cognitive function by activating the PKC-GAP-43-CaMK signal transduction pathway.

GAP-43 and BASP1 in Axon Regeneration: Implications for the Treatment of Neurodegenerative Diseases

“…Several investigations into understanding the mechanism of potential therapies have identified GAP-43 as either upregulated or essential for its ameliorative effects. Levetiracetam for treatment of retinopathy ( Mohammad et al, 2019 ) as well as for the repair of convulsant- induced cognitive impairment ( Wang et al, 2019a ) directly signals through the PKC/GAP-43 signaling pathway. Similarly, TGN-020 for treatment of spinal cord injury ( Li et al, 2019b ), and senegenin for the potential treatment for Aβ-induced neurotoxicity ( Jesky and Chen, 2016 ), involve upregulation of GAP-43 protein levels for both neuroprotection and in vitro regeneration.…”

Translational Informatics for Natural Products as Antidepressant Agents

“…In addition, Wang et al also showed similar results. By injection of Raleigh Alvin (rolipram), which is an inhibitor for phosphoric acid lipase 2–4 (PDE4) that can prevent the hydrolysis of cAMP, the researchers found the increased level of cAMP and phosphorylated CREB, and reduce of immobile time of the mice ( Wang et al, 2019 ). Notably, the cAMP and MAPK signaling partially share the same proteins in depression development.…”

Evaluation of the concentration of growth associated protein-43 and glial cell-derived neurotrophic factor in degenerated intervertebral discs of the lumbosacral region of the spine

“…[5][6][7] GAP-43, which is also known as neuromodulin, F1, and B-50, is a cytoplasmic protein specific to nerve tissue and one of the principal members of the protein kinase C (PKC) family. 8,9 The GAP-43 gene contains three exons. The first exon encodes the membrane-targeting domain, the second exon encodes a calmodulin-binding domain and a PKC phosphorylation site, and the 5 0 -flanking sequence directs initiation of RNA transcription from several sites.…”