The Latest Articles on Neuronal Survival

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Neuronal Survival.

Title: Rb deficiency, neuronal survival and neurodegeneration: In search of the perfect mouse model
Authors: Saad Omais, Yara E. El Atie, Noël Ghanem
Type: Review
Abstract:
Three decades following the introduction of the first Rb knockout (KO) mouse model, the role of this critical protein in regulating brain development during embryogenesis and beyond remains a major scientific interest. Rb is a tumor suppressor gene known as the master regulator of the G1/S checkpoint and control of cell cycle progression in stem and progenitor cells, but also their differentiated progeny. Here, we review the recent literature about the various Rb conditional Knockout (cKO) and inducible Knockout (iKO) models studied thus far, highlighting how findings should always be interpreted in light of the model and context under inquiry especially when studying the role of Rb in neuronal survival. There is indeed evidence of age-specific, cell type-specific and region-specific effects following Rb KO in the embryonic and the adult mouse brain. In terms of modeling neurodegenerative processes in human diseases, we discuss cell cycle re-entry (CCE) as a candidate mechanism underlying the increased vulnerability of Rb-deficient neurons to cell death. Notably, mouse models may limit the extent to which CCE due to Rb inactivation can mimic the pathological course of these disorders, such as Alzheimer's disease. These remarks ought to be considered in future research when studying the consequences of Rb inactivation on neuronal generation and survival in rodents and their corresponding clinical significance in humans.
Access this article: https://doi.org/10.1016/j.crneur.2023.100074

Title: Vildagliptin restores cognitive function and mitigates hippocampal neuronal apoptosis in cisplatin-induced chemo-brain: Imperative roles of AMPK/Akt/CREB/ BDNF signaling cascades
Authors: Abdulla M.A. Mahmoud, Eman M. Mantawy, Sara A. Wahdan, Ramy M. Ammar, Ebtehal El-Demerdash
Type: Research Article
Abstract:
Cisplatin (CP) is a broad-spectrum antineoplastic agent used to treat many human cancers. Nonetheless, most patients receiving CP suffer from cognitive deficits, a phenomenon termed "chemo-brain". Recently, vildagliptin (Vilda), a DPP-4 inhibitor, has demonstrated promising neuroprotective properties against various neurological diseases. Therefore, the present study aims to investigate the potential neuroprotective properties of Vilda against CP-induced neurotoxicity and elucidate the underlying molecular mechanisms. Chemo-brain was induced in Sprague-Dawley rats by i.p injection of CP at a dose of 5 mg/kg once weekly for four weeks. Vilda was administered daily at a dose (10 mg/kg; P.O) for four weeks. The results revealed that Vilda restored the cognitive function impaired by CP, as assessed by the Morris water maze, Y-maze, and passive avoidance tests.

Moreover, Vilda alleviated the CP-induced neurodegeneration, as shown by toluidine blue staining, besides markedly reduced amyloid plaque deposition, as evidenced by Congo red staining. Notably, Vilda boosted cholinergic neurotransmission through the downregulation of the acetylcholinesterase enzyme. In addition, the neuroprotective mechanisms of Vilda include diminishing oxidative stress by reducing MDA levels while raising GSH levels and SOD activity, repressing neuronal apoptosis as shown by elevated Bcl-2 levels together with diminished Bax and caspase-3 expressions, inhibiting neuroinflammation as shown by decreased GFAP expression, and finally boosting hippocampal neurogenesis and survival by upregulating expressions of BDNF and PCNA. These effects were mainly mediated by activating AMPK/Akt/CREB signaling cascades. In summary, Vilda can be considered a promising candidate for guarding against CP-induced chemo-brain and neurodegeneration, thus improving the quality of life of cancer patients.
Access this article: https://doi.org/10.1016/j.biopha.2023.114238

Title: Role of NKCC1 and KCC2 during hypoxia-induced neuronal swelling in the neonatal neocortex
Authors: Yusuke Takezawa, Rachel Langton, Samuel M. Baule, Miriam Bridget Zimmerman, Stephen Baek, Joseph Glykys
Type: Research Article
Abstract:
Neonatal hypoxia causes cytotoxic neuronal swelling by the entry of ions and water. Multiple water pathways have been implicated in neurons because these cells lack water channels, and their membrane has a low water permeability. NKCC1 and KCC2 are cation-chloride cotransporters (CCCs) involved in water movement in various cell types. However, the role of CCCs in water movement in neonatal neurons during hypoxia is unknown. We studied the effects of modulating CCCs pharmacologically on neuronal swelling in the neocortex (layer IV/V) of neonatal mice (post-natal day 8–13) during prolonged and brief hypoxia. We used acute brain slices from Clomeleon mice which express a ratiometric fluorophore sensitive to Cl− and exposed them to oxygen-glucose deprivation (OGD) while imaging neuronal size and [Cl−]i by multiphoton microscopy. Neurons were identified using a convolutional neural network algorithm, and changes in the somatic area and [Cl−]i were evaluated using a linear mixed model for repeated measures. We found that (1) neuronal swelling and Cl− accumulation began after OGD, worsened during 20 min of OGD, or returned to baseline during reoxygenation if the exposure to OGD was brief (10 min). (2) Neuronal swelling did not occur when the extracellular Cl− concentration was low. (3) Enhancing KCC2 activity did not alter OGD-induced neuronal swelling but prevented Cl− accumulation; (4) blocking KCC2 led to an increase in Cl− accumulation during prolonged OGD and aggravated neuronal swelling during reoxygenation; (5) blocking NKCC1 reduced neuronal swelling during early but not prolonged OGD and aggravated Cl− accumulation during prolonged OGD; and (6) treatment with the “broad” CCC blocker furosemide reduced both swelling and Cl− accumulation during prolonged and brief OGD, whereas simultaneous NKCC1 and KCC2 inhibition using specific pharmacological blockers aggravated neuronal swelling during prolonged OGD. We conclude that CCCs, and other non-CCCs, contribute to water movement in neocortical neurons during OGD in the neonatal period.
Access this article: https://doi.org/10.1016/j.nbd.2023.106013

Title: Inhibition of PI3K/Akt/mTOR signaling by NDRG2 contributes to neuronal apoptosis and autophagy in ischemic stroke
Authors: Yuanyuan Wang, Bo Wang, Yuanyuan Liu, Yansong Guo, Hui Lu, Hui Lu
Type: Research Article
Abstract:
Background
Astrocytic N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, has been involved in the cause of ischemic stroke (IS). However, its downstream effector in IS remains unclear. This study aimed to characterize expression of NDRG2 in IS patients and rats and to investigate the underlying mechanism.

Methods
The protein expression of NDRG2 and mammalian target of the rapamycin (mTOR) and the extent of mTOR phosphorylation in plasma of IS patients were detected by ELISA. An oxygen-glucose deprivation model was established in mouse neuronal cells CATH.a, followed by cell counting kit-8, flow cytometry, TUNEL, and western blot assays to examine cell viability, apoptosis and autophagy. Finally, the effect of NDRG2-mediated phosphatidylinositol 3-kinase/protein kinase-B/mTOR (PI3K/AKT/mTOR) pathway on neuronal apoptosis and autophagy was verified in rats treated with middle cerebral artery occlusion.

Results
NDRG2 was highly expressed in the plasma of IS patients, while the extent of mTOR phosphorylation was reduced in IS patients. NDRG2 blocked the PI3K/Akt/mTOR signaling through dephosphorylation. Depletion of NDRG2 suppressed apoptosis and autophagy in CATH.a cells, which was reversed by a dual inhibitor of PI3K and mTOR, BEZ235. In vivo experiments confirmed that NDRG2 promoted neuronal apoptosis and autophagy by dephosphorylating and blocking the PI3K/Akt/mTOR signaling.

Conclusion
The present study has shown that NDRG2 impairs the PI3K/Akt/mTOR pathway via dephosphorylation to promote neuronal apoptosis and autophagy in IS. These findings provide potential targets for future clinical therapies for IS.
Access this article: https://doi.org/10.1016/j.jstrokecerebrovasdis.2023.106984

Title: Baicalin attenuates chronic unpredictable mild stress-induced hippocampal neuronal apoptosis through regulating SIRT1/PARP1 signaling pathway
Authors: Zhongxuan Ma, Dingding Feng, Wenjuan Rui, Zhiqing Wang
Type: Research Article
Abstract:
Baicalin (BA), a flavonoid glycoside extracts from Scutellaria baicalensis Georgi, has been reported to exert antidepressant effects. Emerging evidence indicates that neuronal apoptosis plays a crucial role in the pathogenesis of depression. Poly (ADP-ribose) polymerase-1 (PARP1) is established as a key regulator of the cellular apoptosis. In the present study, we explored whether BA exerts antidepressant effects by regulating PARP1 signaling pathway and elucidated the underlying mechanisms. We found that administration of BA (30 mg/kg, 60 mg/kg) alleviated chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors by increasing sucrose consumption in sucrose preference test (SPT), improving activity status in open field test (OFT) and reducing rest time in tail suspension test (TST). Hematoxylin and eosin (HE) staining and Nissl staining showed that BA ameliorated CUMS-induced neuronal damage in the hippocampus. Moreover, BA significantly upregulated anti-apoptotic protein Bcl-2, downregulated pro-apoptotic protein Bax and cleaved-caspase-3 after CUMS in hippocampal of mice. Intriguingly, western blot and immunohistochemistry (IHC) results showed that the protein level of PARP1 was significantly increased in hippocampal tissue after CUMS, which was reversed by BA treatment. In primary hippocampal neurons (PHNs), BA abrogated the neuronal apoptosis caused by PARP1 overexpression. Meanwhile, BA significantly increased the protein level of SIRT1, SIRT1 inhibitor (EX-527) treatment reversed the effect of BA on reducing the protein level of PARP1 and neuronal apoptosis in CUMS-induced mice. Overall, our results indicated that BA attenuated the CUMS-induced hippocampal neuronal apoptosis through regulating the SIRT1/PARP1 signaling pathway.
Access this article: https://doi.org/10.1016/j.bbr.2023.114299