Updating the guidelines for data transparency in the British Journal of Pharmacology – data sharing and the use of scatter plots instead of bar charts

Background and Purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin‐induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin‐induced cytotoxicity, on the TRPC3‐Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin‐induced systemic tissue wasting in mice. Experimental Approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT‐PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key Results Ibudilast, an anti‐asthmatic drug, attenuated ROS‐mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and Implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

Section: Plasmid Dnamentioning

confidence: 91%

Ibudilast attenuates doxorubicin‐induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes

Nishiyama

Numaga‐Tomita

Fujimoto

et al. 2019

“…The data and statistical analysis in this study comply with the recommendations of the British Journal of Pharmacology on experimental design and analysis in pharmacology (Curtis et al, 2018) and data sharing and presentation in preclinical pharmacology George et al, 2017). The results obtained were expressed as the mean ± SEM.…”

Section: Data and Statistical Analysismentioning

confidence: 91%

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

Background and purpose Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice. Experimental approach Aβ1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ1–42 injection or IN 5 and 12 days after Aβ1–42 injection. After 7 and 14 days of Aβ1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. Key results Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. Conclusion and implications These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

“…The number (n) of independent experiments was initially set to 5; however, some data sets are n = 4 due to technical problems when labelling the receptor and/or due to limited amounts of the compounds. Data are presented as bar graphs only when a scatter plot did not reveal any unusual or interesting aspect of the data, complying with current recommendations (George et al, 2017). TR-FRET data are expressed as the acceptor/donor ratio or normalized to % of maximal Aβ-FAM binding.…”

Section: Data and Statistical Analysismentioning

confidence: 99%

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

Background and Purpose Progressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. Experimental Approach We developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction. Key Results We demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738. Conclusions and Implications Our TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc