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Increased hippocampal TrkA expression ameliorates cranial radiation?induced neurogenesis impairment and cognitive deficit via PI3K/AKT signaling.

ABSTRACT: Cognitive deficit is one of the most serious complications of cranial radiotherapy of head and neck cancers. However, the underlying mechanism of this cognitive impairment remains unclear. In the present study, the role of tropomyosin receptor kinase A (TrkA) and its ligand neurotrophin nerve growth factor (NGF) were investigated following whole?brain irradiation (WBI). Young male Sprague?Dawley rats underwent WBI at a single dose of 10 Gy. WBI was determined to result in notable memory decline and substantial neurogenesis impairment in the hippocampus 3 months post?irradiation. Compared with the control group, TrkA protein expression was greater in irradiated rats 1 week after WBI, which then decreased significantly by the 3?month time?point. However, no difference in NGF expression was observed from 1 day to 3 months post?WBI. Overexpression of hippocampal TrkA in rats using adeno?associated virus ameliorated memory decline induced by irradiation. Additionally, upregulating TrkA expression rescued irradiation?induced hippocampal precursor cell proliferation and promoted neurogenesis. PI3K, Akt and ERK1/2 phosphorylation were also revealed to be significantly inhibited by WBI, which was ameliorated by TrkA overexpression. Findings of the present study indicated that the TrkA?dependent signaling pathway may serve a critical role in radiotherapy?induced cognitive deficit and impairments in neurogenesis.

SUBMITTER: Ji S

PROVIDER: S-EPMC7640353 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Increased hippocampal TrkA expression ameliorates cranial radiation‑induced neurogenesis impairment and cognitive deficit via PI3K/AKT signaling.

Ji Shengjun S Wu Haohao H Ding Xin X Chen Qingqing Q Jin Xing X Yu Jinming J Yang Ming M

Oncology reports 20200928 6

Cognitive deficit is one of the most serious complications of cranial radiotherapy of head and neck cancers. However, the underlying mechanism of this cognitive impairment remains unclear. In the present study, the role of tropomyosin receptor kinase A (TrkA) and its ligand neurotrophin nerve growth factor (NGF) were investigated following whole‑brain irradiation (WBI). Young male Sprague‑Dawley rats underwent WBI at a single dose of 10 Gy. WBI was determined to result in notable memory decline ...[more]

PMID: 33125501

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Project description:Radiation-induced impairment of neurogenesis in the hippocampal dentate gyrus is a concern due to its reported association with cognitive detriments after radiotherapy for brain cancers and the possible risks to astronauts chronically exposed to space radiation. Here, we have extended our recent work in a mouse model of impaired neurogenesis after exposure to low-linear energy transfer (LET) radiation to heavy ion irradiation. To our knowledge, this is the first report of a predictive mathematical model of radiation-induced changes to neurogenesis for a variety of radiation types after acute or fractionated irradiation. We used a system of nonlinear ordinary differential equations (ODEs) to represent age, time after exposure and dose-dependent changes to several cell populations participating in neurogenesis, as reported in mouse experiments. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation in altering neurogenesis: 1. neural stem cells (NSCs); 2. neuronal progenitor cells or neuroblasts (NB); 3. immature neurons (ImN); and 4. glioblasts (GB), with additional consideration of microglial activation. The model describes the negative feedback regulation on early and late neuronal proliferation after irradiation, and the dynamics of the age dependence of neurogenesis. We compared our model to experimental data for X rays, and protons, carbon and iron particles, including data for fractionated iron-particle irradiation. Heavy-ion irradiation is predicted to lead to poor recovery or no recovery from impaired neurogenesis at doses as low as 0.5 Gy in mice. This is only partially ameliorated by dose fractionation, which suggests important implications for Hardon therapy near the Bragg peak, and possibly for space radiation exposures as well. Predictions of the threshold doses where neurogenesis recovery fails for given radiation types are described, and the role of subthreshold transient impairments are briefly discussed.

Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. Histone deacetylase 6 (HDAC6) alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-?1-induced EMT (epithelial-mesenchymal transition). However, the role of HDAC6 in pulmonary fibrosis is unknown. METHODS:HDAC6 expression in IPF and control lungs was assessed by quantitative real-time PCR (qRT-PCR) and immunoblots. Lung fibroblasts were treated with TGF-?1 ± HDAC6 inhibitors (Tubacin, Tubastatin, ACY1215, or MC1568), and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin (oropharyngeal aspiration; single dose) ± Tubastatin (intraperitoneally injection; daily for 21 days), and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type (WT) and knockout (KO) mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS:HDAC6 expression was deregulated in IPF lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-?1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased Akt phosphorylation and increased Akt-PHLPP (PH domain and Leucine rich repeat Protein Phosphatase) association. Tubastatin repressed TGF-?1-induced S6K phosphorylation, HIF-1? expression, and VEGF expression. Tubastatin also repressed TGF-?1-induced inhibition of LC3B-II (a marker of autophagosome formation). In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-?1-induced collagen expression in lung fibroblasts. CONCLUSIONS:HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-?1-induced collagen expression, by diminishing Akt phosphorylation and regulating downstream targets such as HIF-1?-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates pulmonary fibrosis, by targeting the TGF?-PI3K-Akt pathway, likely via an HDAC6-independent mechanism.

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Increased hippocampal TrkA expression ameliorates cranial radiation?induced neurogenesis impairment and cognitive deficit via PI3K/AKT signaling.

Publications

Increased hippocampal TrkA expression ameliorates cranial radiation‑induced neurogenesis impairment and cognitive deficit via PI3K/AKT signaling.

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