Bee venom (Apis mellifera L.) rescues zinc oxide nanoparticles induced neurobehavioral and neurotoxic impact via controlling neurofilament and GAP-43 in rat brain.

This study investigated the possible beneficial role of the bee venom (BV, Apis mellifera L.) against zinc oxide nanoparticles (ZNPs)-induced neurobehavioral and neurotoxic impacts in rats. Fifty male Sprague Dawley rats were alienated into five groups. Three groups were intraperitoneally injected distilled water (C 28D group), ZNPs (100 mg/kg b.wt) (ZNPs group), or ZNPs (100 mg/kg.wt) and BV (1 mg/ kg.bwt) (ZNPs + BV group) for 28 days. One group was intraperitoneally injected with 1 mL of distilled water for 56 days (C 56D group). The last group was intraperitoneally injected with ZNPs for 28 days, then BV for another 28 days at the same earlier doses and duration (ZNPs/BV group). Depression, anxiety, locomotor activity, spatial learning, and memory were evaluated using the forced swimming test, elevated plus maze, open field test, and Morris water maze test, respectively. The brain contents of dopamine, serotonin, total antioxidant capacity (TAC), malondialdehyde (MDA), and Zn were estimated. The histopathological changes and immunoexpressions of neurofilament and GAP-43 protein in the brain tissues were followed. The results displayed that BV significantly decreased the ZNPs-induced depression, anxiety, memory impairment, and spatial learning disorders. Moreover, the ZNPs-induced increment in serotonin and dopamine levels and Zn content was significantly suppressed by BV. Besides, BV significantly restored the depleted TAC but minimized the augmented MDA brain content associated with ZNPs exposure. Likewise, the neurodegenerative changes induced by ZNPs were significantly abolished by BV. Also, the increased neurofilament and GAP-43 immunoexpression due to ZNPs exposure were alleviated with BV. Of note, BV achieved better results in the ZNPs + BV group than in the ZNPs/BV group. Conclusively, these results demonstrated that BV could be employed as a biologically effective therapy to mitigate the neurotoxic and neurobehavioral effects of ZNPs, particularly when used during ZNPs exposure.

GAP-43 Induces the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Retinal Ganglial-Like Cells.

Optic neuritis (ON) is a common neurological disease, and the transplant of retinal ganglion cells (RGCs) has been thought as a promising strategy for improving the injury of the optic nerve system. Bone mesenchymal stem cells (BMSCs) have the potential to differentiate into neural cells. Several studies have indicated that GAP-43 is related with the regeneration of nerve cells, while the effect of GAP-43 on inducing BMSC differentiation remains unclear. In this study, the BMSCs were separated from the rats and identified with flow cytometry assay. The GAP-43 expressed vectors were transfected into the BMSCs, and the biomarkers of RGCs such as PAX6, LHX2, and ATOH7 were used to observe by qRT-PCR. Moreover, the effect of GAP-43-induced BMSCs (G-BMSCs) on ON improvement was also verified with rat models, and the activity of MAPK pathway was measured with western blot. Here, it was found that GAP-43 could obviously promote the differentiation of BMSCs, and increased PAX6, LHX2, ATOH7, BRN3A, and BRN3B were observed in the process of cell differentiation. Moreover, it was also found that G-BMSCs significantly increased the abundances of NFL and NFM in G-BMSCs, and GAP-43 could also enhance the activity of MAPK pathways in BMSCs. Therefore, this study suggested that GAP-43 could induce the differentiation of bone marrow-derived mesenchymal stem cells into retinal ganglial cells.

Learning and memory impairment induced by 1,4-butanediol is regulated by ERK1/2-CREB-BDNF signaling pathways in PC12 cells.

1,4-butanediol (1,4-BD) is a known γ-hydroxybutyric acid (GHB) precursor which affects the nervous system after ingestion, leading to uncontrolled behavioral consequences. In the present study, we investigated whether 1,4-BD induces oxidative stress and inflammation in PC12 cells and evaluated the toxic effects of 1,4-BD associates with learning and memory. CCK-8 results revealed a dose-effect relationship between the cell viability of PC12 cells and 1,4-BD when the duration of action was 2 h or 4 h. Assay kits results showed that 1,4-BD decreased the levels of Glutathione (GSH), Glutathione peroxidase (GSH-px), Superoxide dismutase (SOD), Acetylcholine (Ach) and increased the levels of Malondialdehyde (MDA), Nitric oxide (NO) and Acetylcholinesterase (AchE). Elisa kits results indicated that 1,4-BD decreased the levels of synaptophysin I (SYN-1), Postsynaptic density protein-95 (PSD-95), Growth associated protein-43 (GAP-43) and increased the levels of Tumor necrosis factor alpha (TNF-α) and Interleukin- 6 (IL-6). RT-PCR results showed that the mRNA levels of PSD-95, SYN-1 and GAP-43 were significantly decreased. The expression of phosphorylation extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), phosphorylation cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) proteins were significantly decreased in PC12 cells by protein blotting. Overall, these results suggest that 1,4-BD may affect synaptic plasticity via the ERK1/2-CREB-BDNF pathway, leading to Ach release reduction and ultimately to learning and memory impairment. Furthermore, oxidative stress and inflammation induced by 1,4-BD may also result in learning and memory deficits. These findings will enrich the toxicity data of 1.4-BD associated with learning and memory impairment.

Regulation of Neurogenesis and Neuronal Differentiation by Natural Compounds.

Neuronal damage or degeneration is the main feature of neurological diseases. Regulation of neurogenesis and neuronal differentiation is important in developing therapies to promote neuronal regeneration or synaptic network reconstruction. Neurogenesis is a multistage process in which neurons are generated and integrated into existing neuronal circuits. Neuronal differentiation is extremely complex because it can occur in different cell types and can be caused by a variety of inducers. Recently, natural compounds that induce neurogenesis and neuronal differentiation have attracted extensive attention. In this paper, the potential neural induction effects of medicinal plant-derived natural compounds on neural stem/progenitor cells (NS/PCs), the cultured neuronal cells, and mesenchymal stem cells (MSCs) are reviewed. The natural compounds that are efficacious in inducing neurogenesis and neuronal differentiation include phenolic acids, polyphenols, flavonoids, glucosides, alkaloids, terpenoids, quinones, coumarins, and others. They exert neural induction effects by regulating signal factors and cellspecific genes involved in the process of neurogenesis and neuronal differentiation, including specific proteins (ß-tubulin III, MAP-2, tau, nestin, neurofilaments, GFAP, GAP-43, NSE), related genes and proteins (STAT3, Hes1, Mash1, NeuroD1, notch, cyclin D1, SIRT1, Reggie-1), transcription factors (CREB, Nkx-2.5, Ngn1), neurotrophins (BDNF, NGF, NT-3), and signaling pathways (JAK/STAT, Wnt/ß-catenin, MAPK, PI3K/Akt, GSK-3ß/ß-catenin, Ca2+/CaMKII/ATF1, Nrf2/HO-1, BMP).The natural compounds with neural induction effects are of great value for neuronal regenerative medicine and provide promising prevention and treatment strategies for neurological diseases.

Small proteins that modulate calmodulin-dependent signal transduction: effects of PEP-19, neuromodulin, and neurogranin on enzyme activation and cellular homeostasis.

Neuromodulin (GAP-43), neurogranin (RC3), and PEP-19 are small acid-stable proteins that bind calcium-poor calmodulin through a loosely conserved IQ-motif. Even though these proteins have been known for many years, much about their function in cells is not understood. It has recently become appreciated that calmodulin activity in cells is tightly controlled and that pools of otherwise free calmodulin are sequestered so as to restrict its availability for activating calcium/calmodulin-dependent enzymes. Neuromodulin, neurogranin, and PEP-19 appear to be major participants in this type of regulation. One way in which they do this is by providing localized increases in the concentration of calmodulin in cells so that the maximal level of target activation is increased. Additionally, they can function as calmodulin antagonists by directly inhibiting the association of calcium/calmodulin with enzymes and other proteins. Although neuromodulin, neurogranin, and PEP-19 were early representatives of the small IQ-motif-containing protein family, newer examples have come to light that expand the number of cellular systems through which the IQ-peptide/calmodulin interaction could regulate biological processes including gene transcription. It is the purpose of this review to examine the behavior of neuromodulin, neurogranin, and PEP-19 in paradigms that include both in vitro and in situ systems in order to summarize possible biological consequences that are linked to the expression of this type of protein. The use of protein:protein interaction chromatography is also examined in the recovery of a new calmodulin-binding peptide, CAP-19 (ratMBF1). Consistent with earlier predictions, at least one function of small IQ-motif proteins appears to be that they lessen the extent to which calcium-calmodulin-dependent enzymes become or stay activated. It also appears that these polypeptides can function to selectively inhibit activation of intracellular targets by some agonists while simultaneously permitting activation of these same targets by other agonists. Much of the mechanism for how this occurs is unknown, and possible explanations are examined. One of the biological consequences for a cell that expresses a calmodulin-regulatory protein could be an increased resistance to calcium-mediated toxicity. This possibility is examined for cells expressing PEP-19 and both anatomical and cell-biological data is described. The study of IQ-motif-containing small proteins has stimulated considerable thought as to how calcium signaling is refined in neurons. Current evidence suggests that signaling through calmodulin is not a fulminating and homogenous process but a spatially limited and highly regulated one. Data from studies on neuromodulin, neurogranin, and PEP-19 suggest that they play an important role in establishing some of the processes by which this regulation is accomplished.