Molecular mechanism of Rolupram reducing neuroinflammation in noise induced tinnitus mice through TLR4/NF kB/NLRP3 protein/caspase-1/IL-1 β signaling pathway

Article

Author: Lin, Shitong ; Wu, Jiahui ; Hu, Yulin ; Nong, Fengjing ; Hu, Guoli ; Lu, Cheng ; Chen, Rongbin ; Luo, Lixia

Noisy tinnitus is a common auditory system disease characterized by persistent tinnitus symptoms. The TLR4/NF - κ B/NLRP3 signaling pathway plays an important role in neuroinflammatory response. Select 6 control and 6 noise exposed mice for transcriptome sequencing analysis in the hippocampus, conduct high-throughput data analysis, identify differentially expressed genes, and screen for pathways. Auditory brainstem response (ABR) detection was performed to understand the hearing changes, and the modeling effect was evaluated using the GPIAS% inhibition experiment of auditory startle reflex. Morphological observation of the basement membrane was performed to determine whether the inner hair cells were damaged. Immunohistochemistry and immunofluorescence were used to determine the activation of microglia in the hippocampus of noise induced tinnitus mice. Finally, qPCR and Western Blot were used to detect the expression of TLR4, NF kB, NLRP3, caspase-1, and IL-1 β in the hippocampus of each group of mice. Through high-throughput data analysis, it was found that there was no significant difference in the auditory threshold of the three groups of mice; After 2 h of exposure to 100 dB SPL noise, the GPIAS% of mice decreased significantly compared to before exposure, and membrane construction was successful. After 7 days, the GPIAS% of the drug intervention group increased. After noise exposure, mice developed tinnitus, and hippocampus neuroinflammation. Roflupram can inhibit neuroinflammation and improve tinnitus through the TLR4/NF kB/NLRP3/caspase-1/IL-1 β signaling pathway.

01 Jan 2024·Neuropharmacology

Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis

Article

Author: Zhang, Wenmo ; Wang, Ying ; Zhang, Chunting ; Zhang, Dongmei ; Wang, Ming ; Su, Xiaoli ; Wang, Di ; Han, Ling ; Liu, Qiaochu ; Huo, Di ; Feng, Honglin ; Cong, Chaohua ; Tan, Xingli ; Wang, Hongyong ; Liang, Weiwei

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3-5 years. Defective autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior horn of the spinal cord, activated the AMPK/ULK1 signaling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A, ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated that ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that ROF is neuroprotective in ALS models and the AMPK/ULK1 signaling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation.

01 Oct 2023·Alternative therapies in health and medicine

Phosphodiesterase 4 Inhibitor Roflupram Suppresses Inflammatory Responses Using Reducing Inflammasome in Microglia After Spinal Cord Injury.

Article

Author: Qi, Huiping ; Zhou, Jinlong ; Zhao, Tianshu ; Qian, Guibin ; Sun, Piyun

ContextNeuroinflammation after spinal cord injury (SCI) can lead to long-term damage in neural tissue, which can cause the destruction and dysfunction of the neurological system. Roflupram (ROF), a selective phosphodiesterase 4 inhibitor, may play a protective role against neuropathological diseases, but the specific role of ROF in SCI treatment is unknown.ObjectiveThe study intended to investigate the anti-inflammatory mechanism and therapeutic effects of ROF to determine if it can attenuate lipopolysaccharide (LPS)-induced microglia that induces neuroinflammation and decrease neural-tissue damage following an SCI.DesignThe research team performed an animal study.SettingThe study took place at the Fourth Affiliated Hospital of Harbin Medical University in Harbin, China.AnimalsThe animals were female C57BL/6 mice, aged 8 weeks and weighing approximately 20 g.InterventionFor the in-vitro study, the research team divided BV2 microglial cells into three groups: (1) the control group, which received no LPS stimuli and no ROF treatment, (2) the LPS group, which received LPS stimuli but no ROF treatment, and (3) LPS+ROF group, which received both LPS stimuli and ROF treatment. For the in-vivo study, the research team randomly divided the mice into three groups: (1) the sham group, for which the team didn't induce SCI and which received no ROF treatment (2) the SCI group, for which the team induced SCI but which received no ROF treatment, and (3) the SCI+ROF group, for which the team induced SCI and which received the ROF treatment.Outcome MeasuresThe research team evaluated: (1) the cell viability of the BV2 microglia cells after five doses of ROF and the RNA levels of inflammatory-activation-related factors, the inflammatory pathway; (2) in-vitro inhibition of inflammation in LPS-activated microglia; (3) the anti-neuroinflammatory role of ROF after SCI induction in vitro; and (4) the role of ROF in neural-structure protection and locomotor-function recovery in vitro.ResultsIn the in-vitro study, the ROF attenuated microglial inflammation through the inhibition of the NLRP3 inflammasome in vitro, reduced neuroinflammation, and protected against neuronal loss. In the in-vivo study with mice, the ROF: (1) improved the functional recovery of locomotor skills after induction of SCI; (2) acted in an anti-inflammatory role in SCI, restraining microglial inflammation by inhibition of the "nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3" (NLRP3) inflammasome and reduction of caspase-1-dependent, interleukin-1 beta (IL)-1β; and (3) reduced neuronal death and protected against tissue loss, improving functional recovery after an SCI.ConclusionsThe current study demonstrated that ROF can reduce the levels of inflammation in the tissue after spinal cord injury by modulating the AMPK/NLRP3 signaling pathway, thereby promoting the recovery of motor function in mice. ROF is a promising drug for prevention of neural-tissue damage following neural injury.

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Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Preclinical	United States	Georgia State University	25 Dec 2008

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