Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

Cai, Bangrong; Seong, Kyung-Joo; Bae, Sun-Woong; Kook, Min Suk; Chun, Changbum; Lee, Jin Ho; Choi, Wonseok; Jung, Ji‐Yeon; Kim, Wonjae

doi:10.1007/s12035-019-1496-3

Cited by 19 publications

(8 citation statements)

References 54 publications

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“…For example, inducing sepsis in rats by CLP surgery disturbs adult neurogenesis in the subventricular zone [25]. Lipopolysaccharide-induced neuroinflammation in mice decreases immature and mature neuronal differentiation of neural stem cells and reduces neural stem cell proliferation and survival in adult hippocampal dentate gyrus [26]. Therefore, we speculate that sepsis-induced decline in learning and memory in CLP mice may be triggered by deficits in hippocampal neurogenesis.…”

Section: Discussionmentioning

confidence: 92%

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

Yin

Shen

et al. 2020

J Neuroinflammation

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Background Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function. Methods Sepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8–12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence. Results CLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown. Conclusion SOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

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Section: Discussionmentioning

confidence: 92%

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

Yin

Shen

et al. 2020

J Neuroinflammation

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“…More precisely, chronic LPS reduces the dendritic length and postsynaptic cluster density of immature new‐born granule cells in the hippocampus in mice (Llorens‐Martín et al, 2014). This is also observed after IFN‐α injection, which alters hippocampal cell proliferation (Cai et al, 2019; Kaneko et al, 2006; Zheng et al, 2014), survival (Cai et al, 2019) and neuronal differentiation (Zheng et al, 2014) in both rats and mice.…”

Section: Neuroinflammation and Main Neurobiological Mechanisms Of Depmentioning

confidence: 87%

Neuroinflammation and depression: A review

Troubat

Barone

Leman

et al. 2020

Eur J of Neuroscience

534

301

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“…Arg-DG can also rescue hippocampal neurogenesis and cognitive function impaired by LPS via the inhibition of microglial overactivation, the expression of the TLR4 receptor and downstream signaling of NF-κB and JNK/MAPK, and the ultimate suppression of proinflammatory cytokines. Our results suggested that the chemical modification of DG might be an effective approach to improve its physicochemical properties and pharmacological activities in neurodegenerative disorders resulting from microglia-mediated neuroinflammation [84]. Interestingly, although the DG glycoside and DG derivatives including DGP and Arg-DG exhibited strong anti-inflammatory activity in LPS-induced microglial BV2 cells, they differed in inhibitory activity against MAPK signaling.…”

Section: Pharmacological Activity and Mechanism Of Diosgenin And Its mentioning

confidence: 87%

“…Recently, we reported that DG derivatives carrying primary amine (Compound 7, DGP) or the amino acid Larginine (Compound 4, Arg-DG) at the C3 show a significant increase in aqueous solubility and anti-inflammatory activity in LPS-induced BV2 cells compared to DG. The possible mechanisms of both derivatives involve the inhibition of NF-κB activation and JNK/MAPK signaling [57,84]. Arg-DG can also rescue hippocampal neurogenesis and cognitive function impaired by LPS via the inhibition of microglial overactivation, the expression of the TLR4 receptor and downstream signaling of NF-κB and JNK/MAPK, and the ultimate suppression of proinflammatory cytokines.…”

Section: Pharmacological Activity and Mechanism Of Diosgenin And Its mentioning

confidence: 99%

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Cai

Zhang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson’s disease, Alzheimer’s disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

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Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

Cited by 19 publications

References 54 publications

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

Neuroinflammation and depression: A review

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

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