Induction of cellular senescence as a late effect and BDNF-TrkB signaling-mediated ameliorating effect on disruption of hippocampal neurogenesis after developmental exposure to lead acetate in rats

Yamashita, Risako; Takahashi, Yasunori; Takashima, Kazumi; Okano, Hiromu; Ojiro, Ryota; Tang, Qian; Kikuchi, Shunsuke; Kobayashi, Mio; Ogawa, Bunichiro; Jin, Minghua; Kubota, Reiji; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto

doi:10.1016/j.tox.2021.152782

Cited by 9 publications

(3 citation statements)

References 65 publications

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“…Moreover, TrkB receptors can also be transactivated via cross-talk with certain G-protein-coupled receptors, such as EGF ( Puehringer et al, 2013 ) and adenosine A2a receptors ( Lee and Chao, 2001 ). Lastly, TrkB signaling can be elevated by increasing Ntrk2 gene expression ( Yamashita et al, 2021 ). It will be of interest to pursue experiments to investigate whether these mechanisms are involved in Kv1.1-dependent postnatal neurogenesis in mouse hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Kv1.1 channels regulate early postnatal neurogenesis in mouse hippocampus via the TrkB signaling pathway

Chou

Huang

et al. 2021

eLife

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In the postnatal brain, neurogenesis occurs only within a few regions, such as the hippocampal sub-granular zone (SGZ). Postnatal neurogenesis is tightly regulated by factors that balance stem cell renewal with differentiation, and it gives rise to neurons that participate in learning and memory formation (Anacker and Hen, 2017; Bond et al., 2015; Toda et al., 2019). The Kv1.1 channel, a voltage-gated potassium channel, was previously shown to suppress postnatal neurogenesis in the SGZ in a cell-autonomous manner. In this study, we clarified the physiological and molecular mechanisms underlying Kv1.1-dependent postnatal neurogenesis. First, we discovered that the membrane potential of neural progenitor cells is highly dynamic during development. We further established a multinomial logistic regression model for cell type classification based on the biophysical characteristics and corresponding cell markers. We found that loss of Kv1.1 channel activity causes significant depolarization of type 2b neural progenitor cells. This depolarization is associated with increased tropomyosin receptor kinase B (TrkB) signaling and proliferation of neural progenitor cells; suppressing TrkB signaling reduces the extent of postnatal neurogenesis. Thus, our study defines the role of the Kv1.1 potassium channel in regulating the proliferation of postnatal neural progenitor cells in the mouse hippocampus.

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Section: Discussionmentioning

confidence: 99%

Kv1.1 channels regulate early postnatal neurogenesis in mouse hippocampus via the TrkB signaling pathway

Chou

Huang

et al. 2021

eLife

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“…Pb exposure in animal models increased G1 cell cycle arrest in hematopoietic stem cells and increased the expression of SA-β-Gal in CD90 + CD45 - cells following low-dose exposure to Pb [ 171 ]. Studies utilizing rat models observed increased gene expression of SASP inflammatory cytokines (IL-1α, IL-1β, IL-6, and IL-8) in pups whose mothers had been treated with 0, 2000, or 4000 ppm lead acetate during gestation [ 172 ]. This study also reported senescence-associated changes in cells of the subgranular zone, with decreased expression of Pcna and Apex1 mRNA levels (correlated with cell proliferation), increased expression of Chek1 and Cdknc1c mRNA levels (cell cycle arrest marker), and increased expression of γH 2 AX protein levels (DNA damage markers).…”

Section: Heavy Metals Induce Cellular Senescencementioning

confidence: 99%

Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

Vielee

Wise

2023

Brain Sciences

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Advancements in modern medicine have improved the quality of life across the globe and increased the average lifespan of our population by multiple decades. Current estimates predict by 2030, 12% of the global population will reach a geriatric age and live another 3–4 decades. This swelling geriatric population will place critical stress on healthcare infrastructures due to accompanying increases in age-related diseases and comorbidities. While much research focused on long-lived individuals seeks to answer questions regarding how to age healthier, there is a deficit in research investigating what aspects of our lives accelerate or exacerbate aging. In particular, heavy metals are recognized as a significant threat to human health with links to a plethora of age-related diseases, and have widespread human exposures from occupational, medical, or environmental settings. We believe heavy metals ought to be classified as a class of gerontogens (i.e., chemicals that accelerate biological aging in cells and tissues). Gerontogens may be best studied through their effects on the “Hallmarks of Aging”, nine physiological hallmarks demonstrated to occur in aged cells, tissues, and bodies. Evidence suggests that cellular senescence—a permanent growth arrest in cells—is one of the most pertinent hallmarks of aging and is a useful indicator of aging in tissues. Here, we discuss the roles of heavy metals in brain aging. We briefly discuss brain aging in general, then expand upon observations for heavy metals contributing to age-related neurodegenerative disorders. We particularly emphasize the roles and observations of cellular senescence in neurodegenerative diseases. Finally, we discuss the observations for heavy metals inducing cellular senescence. The glaring lack of knowledge about gerontogens and gerontogenic mechanisms necessitates greater research in the field, especially in the context of the global aging crisis.

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“…ALA consumption alleviates various neuropathological conditions. Studies have found that ALA exhibits anticonvulsant effects, and possible mechanisms may include altering membrane composition of nerve cells, activating peroxisome proliferator-activated receptors, and reducing inflammation (3,4) . However, the results of clinical studies are inconsistent, and there is limited research on the effects and mechanisms of ALA in relation to epilepsy.…”

Section: Introductionmentioning

confidence: 99%

α-Linolenic acid ameliorates pentylenetetrazol-induced neuron apoptosis and neurological impairment in mice with seizures via down-regulating JAK2/STAT3 pathway

Zeng,

Luo,

Cheng

et al. 2024

Br J Nutr

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Epilepsy ranks fourth among neurological diseases, featuring spontaneous seizures and behavioral and cognitive impairments. Although anti-epileptic drugs are currently available clinically, 30% of epilepsy patients are still ineffective in treatment, and 52% of patients experience serious adverse reactions. In this work, the neuroprotective effect of α-linolenic acid (ALA, a nutrient) in mice and its potential molecular mechanisms exposed to pentylenetetrazol was assessed. The mice were injected with pentetrazol 37 mg/kg, and ALA was intra-gastrically administered for 40 days. The treatment with ALA significantly reduced the overall frequency of epileptic seizures and improved the behavior impairment and cognitive disorder caused by pentetrazol toxicity. In addition, ALA can not only reduce the apoptosis rate of brain neurons in epileptic mice, but also significantly reduce the content of brain inflammatory factors (IL-6, IL-1, and TNF-α). Furthermore, we predicted that the possible targets of ALA in the treatment of epilepsy were JAK2 and STAT3 through molecular docking. Finally, through molecular docking and Western Blot studies, we revealed the potential mechanism of ALA ameliorates pentylenetetrazol-induced neuron apoptosis and neurological impairment in mice with seizures by downregulating the JAK2/STAT3 pathway. This study aimed to investigate the antiepileptic and neuroprotective effects of ALA, as well as explore its potential mechanisms, through the construction of a chronic ignition mouse model via intraperitoneal PTZ injection. The findings of this research provide crucial scientific support for subsequent clinical application studies in this field.

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Induction of cellular senescence as a late effect and BDNF-TrkB signaling-mediated ameliorating effect on disruption of hippocampal neurogenesis after developmental exposure to lead acetate in rats

Cited by 9 publications

References 65 publications

Kv1.1 channels regulate early postnatal neurogenesis in mouse hippocampus via the TrkB signaling pathway

Kv1.1 channels regulate early postnatal neurogenesis in mouse hippocampus via the TrkB signaling pathway

Among Gerontogens, Heavy Metals Are a Class of Their Own: A Review of the Evidence for Cellular Senescence

α-Linolenic acid ameliorates pentylenetetrazol-induced neuron apoptosis and neurological impairment in mice with seizures via down-regulating JAK2/STAT3 pathway

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