Roflumilast: A potential drug for the treatment of cognitive impairment?

Sugin, Lal Jabaris S; Arumugam, Murugesan; Menon, Bindu; Narayan, Shyam

doi:10.1016/j.neulet.2020.135281

Cited by 15 publications

(10 citation statements)

References 52 publications

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“…Studies have shown that roflumilast can easily penetrate the brain, correct cognitive disorders, and improve memory 24,39,40 . In a recent study, it was also reported that proinflammatory cytokines decreased due to the increasing amount of cAMP in the brain after roflumilast administration 41 …”

Section: Discussionmentioning

confidence: 98%

Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition

Keskin

Tavacı

et al. 2021

Clin Exp Pharma Physio

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This study aims to investigate the protective effect of roflumilast, a phosphodiesterase (PDE)‐4 enzyme inhibitor, and demonstrate its possible role in the development prevention of cerebral ischemia/reperfusion injury (CI/RI) after stroke induced by carotid artery ligation in juvenile rats. The rats were randomly divided into five groups: healthy group without any treatment, healthy group administered with 1 mg/kg roflumilast, CI group not administered with roflumilast, CI group administered with 0.5 mg/kg roflumilast, and CI group administered with 1 mg/kg roflumilast. In the CI groups, reperfusion was achieved 2h after ischemia induction; in the roflumilast groups, this drug was intraperitoneally administered immediately after reperfusion and at the 12th hour. At the end of 24h, the rats were sacrificed and their brain tissues removed for examination. The mRNA expressions obtained with real‐time PCR of IL‐1β, TNF‐α, and NLRP3 significantly increased in the CI/RI‐induced groups compared with the control group, and this increase was significantly lower in the groups administered with roflumilast compared with the CI/RI‐induced groups. Moreover, ELISA revealed that both IL‐1 β and IL‐6 brain levels were significantly higher in the CI/RI‐induced groups than in the controls. This increase was significantly lower in the groups administered with roflumilast compared with the CI/RI‐induced groups. Histopathological studies revealed that the values closest to those of the healthy group were obtained from the roflumilast groups. Nissl staining revealed that the Nissl bodies manifested normal density in the healthy and roflumilast‐administered healthy groups, but were rare in the CI/RI‐induced groups. Roflumilast treatment increased these decreased Nissl bodies with increasing doses. Observations indicated that the Nissl body density was close to the value in the healthy group in the CI/RI‐induced group administered with 1 mg/kg roflumilast. Overall, roflumilast reduced cellular damage caused by CI/RI in juvenile rats, and this effect may be mediated by NLRP3.

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Section: Discussionmentioning

confidence: 98%

Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition

Keskin

Tavacı

et al. 2021

Clin Exp Pharma Physio

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“…It improved episodic memory in subjects with minimal cognitive impairment at a low non-emetic dose with a plasma level nearly five-fold lower than the dose for chronic obstructive pulmonary disease patients. Using such low doses minimizes typical side effects of PDE4 inhibitors such as vomiting (30). Roflumilast showed a more potent anti-inflammatory activity in both animals and humans and was better tolerated than the preceding PDE4 inhibitors, e.g., rolipram and cilomilast (31).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic colitis was induced by weekly rectal injections of increasing doses of TNBS over 6 weeks (15,30,45,60,60, and 60 mg from day 0 to day 35), as previously described (4,12). Briefly, after food deprivation for 24 h, rats were anesthetized with an intraperitoneal injection of 1% isoflurane.…”

Section: Induction Of Colitis and Treatment Groupsmentioning

confidence: 99%

Rectal roflumilast improves trinitrobenzenesulfonic acid-induced chronic colitis in rats

Shaikh-Omar

Murad

Al-Otaibi

2022

Braz J Med Biol Res

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Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via offlabel routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mgÁkg -1 Áday -1 ), oral roflumilast (5 mgÁkg -1 Á day -1 ), or rectal roflumilast (5 mgÁkg -1 Áday -1 ) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-a, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-a. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-a, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.

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“…Chronic bronchitis symptoms of Ro umilast and are the only PDE4 inhibitor for COPD patients with a history of exacerbation that has reached the market (Baye 2012). Several new PDE4 inhibitor compounds are in early clinical development, and there is not yet clear information about their e cacy and safety (Sugin et al 2020). In preclinical and early-stage studies, it has been reported that PDE4 inhibitors improve memory and have curative effects on depressive-like behaviors caused by chronic mild stress, lipopolysaccharide or ethanol abstinence (Prickaerts, Heckman, and Blokland 2017;Yu et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Examination of Apoptotic and Autophagic Effects of Chronic Roflumilast Use on Rat Testicular Tissue by Immunohistochemical and Immunofluorescence Methods

Gezer

Sarı

2021

Preprint

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Roflumilast (ROF) (3-cyclo-propylmethoxy-4-difuorome-thoxy-N-[3,5-di-chloropyrid-4-yl] benzamide) is a second generation and forcible phosphodiesterase-4 (PDE4) inhibitor. This study aims to investigate the effects of chronic Roflumilast in different doses on testicular tissue and testosterone levels in healthy Sprague-Dawley rats. During the research, the 6 weeks old (180–200 gr), 36 male rats were divided into 4 groups. Roflumilast (ROF) was administered as 0.5 mg/kg and 1 mg/kg by oral gavage for four weeks, once each day. Hematoxylin-Eosin (H&E) staining for histopathological examinations in testicular tissue, immunohistochemical and immunofluorescence examinations for Caspase-3, Apoptosis Inducing Factor (AIF) and Light Chain 3β (LC3B) expression levels, and ELISA method used to determine serum testosterone levels. Data were analyzed using SPSS v.22 with Kruskal-Wallis, Mann Whitney-U, and Wilcoxon tests. Roflumilast group lost weight compared to the control and sham. Shedding in the seminiferous epithelium, degenerations in the interstitial area, separation between cells, desquamation, interstitial edema and degenerative changes in the testicular tissue was observed. While apoptosis and autophagy determined by Caspase-3, AIF and LC3B were close and statistically insignificant in control and sham, there was significantly increased apoptotic and autophagic changes and immunopositivity in the ROF groups. The 1 mg/kg Roflumilast group’s serum testosterone level was lower than control, sham and 0.5 mg/kg Roflumilast groups. When the research data was evaluated, it was determined that the chronic use of the active ingredient Roflumilast, which has a broad-spectrum area such as COPD, arthritis, neurodegenerative diseases, liver and dermatology, had negative effects on the testicular tissue and testosterone level of rats.

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Roflumilast: A potential drug for the treatment of cognitive impairment?

Cited by 15 publications

References 52 publications

Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition

Neuroprotective effect of roflumilast under cerebral ischaemia/reperfusion injury in juvenile rats through NLRP‐mediated inflammatory response inhibition

Rectal roflumilast improves trinitrobenzenesulfonic acid-induced chronic colitis in rats

Examination of Apoptotic and Autophagic Effects of Chronic Roflumilast Use on Rat Testicular Tissue by Immunohistochemical and Immunofluorescence Methods

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