The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia–reperfusion brain injury in mice

Hammarlund, Maria; Darsalia, Vladimer; Mjörnstedt, Filip; Pattanaik, Bagmi; Mallard, Carina; Rocha‐Ferreira, Eridan; Patrone, Cesare; Johansson, Maria

doi:10.1042/bsr20210736

Cited by 4 publications

(8 citation statements)

References 58 publications

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“…37 Conversely, a previous animal study using a stroke model demonstrated that treatment with AR-R17779 did not prevent cerebral ischemia-reperfusions injury. 38 The effects of binding to different receptors than just the α7nAChR need to also be considered. AR-R17779 is reported to be a highly selective agonist of the α7nAChR, with in vitro studies demonstrating 96% efficacy for binding the α7nAChR.…”

Section: Discussionmentioning

confidence: 99%

Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

Costantini¹,

Coimbra²,

Weaver³

et al. 2021

J Trauma Acute Care Surg

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BACKGROUND:The systemic inflammatory response (SIRS) drives late morbidity and mortality after injury. The α7 nicotinic acetylcholine receptor (α7nAchR) expressed on immune cells regulates the vagal anti-inflammatory pathway that prevents an overwhelming SIRS response to injury. Nonspecific pharmacologic stimulation of the vagus nerve has been evaluated as a potential therapeutic to limit SIRS. Unfortunately, the results of clinical trials have been underwhelming. We hypothesized that directly targeting the α7nAchR would more precisely stimulate the vagal anti-inflammatory pathway on immune cells and decrease gut and lung injury after severe burn. METHODS:C57BL/6 mice underwent 30% total body surface area steam burn. Mice were treated with an intraperitoneal injection of a selective agonist of the α7nAchR (AR-R17779) at 30 minutes postburn. Intestinal permeability to 4 kDa FITC-dextran was measured at multiple time points postinjury. Lung vascular permeability was measured 6 hours after burn injury. Serial behavioral assessments were performed to quantify activity levels. RESULTS:Intestinal permeability peaked at 6 hours postburn. AR-R17779 decreased burn-induced intestinal permeability in a dose-dependent fashion ( p < 0.001). There was no difference in gut permeability to 4 kDa FITC-dextran between sham and burn-injured animals treated with 5 mg/kg of AR-R17779. While burn injury increased lung permeability 10-fold, AR-R17779 prevented burn-induced lung permeability with no difference compared with sham ( p < 0.01). Postinjury activity levels were significantly improved in burned animals treated with AR-R17779. CONCLUSION: Directly stimulating the α7nAchR prevents burn-induced gut and lung injury. Directly targeting the α7nAChR that mediates the cholinergic anti-inflammatory response may be an improved strategy compared with nonspecific vagal agonists.

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Section: Discussionmentioning

confidence: 99%

Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

Costantini¹,

Coimbra²,

Weaver³

et al. 2021

J Trauma Acute Care Surg

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“…Stimulation of α7nAChR in adult brain injury models have been tested with PHA 568487 as well as other agonists/PAMs, such as PHA 543613 and PNU 282987, where several studies demonstrate a beneficial effect on injury development [ 15 , 16 , 18 , 19 , 20 , 21 ], while a previous study in our lab showed lack of effect of AR-R17779 in transient MCAO [ 31 ]. The agonist chosen for this study, PHA 568487, has shown promising results in models of adult brain injury [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…The volume of the tissue loss was calculated as V injury = V contra – V ipsi where V = ΣA∙T, A is the MAP2-stained section of the hemisphere at each level and T is the distance between levels (400 µm), including the thickness of the section [ 23 ]. Microglia scoring was performed using a modified version of a previously described scoring system [ 30 , 31 ]. In brief, brain regions, including upper and lower cortex, pyriform cortex, hippocam-pus, midbrain, substantia nigra, thalamus and striatum, were given a score 0-4 based on microglial phenotype and accumulation ( Supplementary Figure S1 ).…”

Section: Methodsmentioning

confidence: 99%

The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury

Hammarlund

Ek²,

Akar³

et al. 2022

Biomedicines

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Inflammation plays a central role in the development of neonatal brain injury. The alpha 7 nicotinic acetylcholine receptor (α7nAChR) can modulate inflammation and has shown promising results as a treatment target in rodent models of adult brain injury. However, little is known about the role of the α7nAChR in neonatal brain injury. Hypoxic-ischemic (HI) brain injury was induced in male and female C57BL/6 mice, α7nAChR knock-out (KO) mice and their littermate controls on postnatal day (PND) 9–10. C57BL/6 pups received i.p. injections of α7nAChR agonist PHA 568487 (8 mg/kg) or saline once daily, with the first dose given directly after HI. Caspase-3 activity and cytokine mRNA expression in the brain was analyzed 24 h after HI. Motor function was assessed 24 and 48 h after HI, and immunohistochemistry was used to assess tissue loss at 24 h and 7 days after HI and microglial activation 7 days after HI. Activation of α7nAChR with the agonist PHA 568487 significantly decreased CCL2/MCP-1, CCL5/RANTES and IL-6 gene expression in the injured brain hemisphere 24 h after HI compared with saline controls in male, but not female, pups. However, α7nAChR activation did not alter caspase-3 activity and TNFα, IL-1β and CD68 mRNA expression. Furthermore, agonist treatment did not affect motor function (24 or 48 h), neuronal tissue loss (24 h or 7 days) or microglia activation (7 days) after HI in either sex. Knock-out of α7nAChR did not influence neuronal tissue loss 7 days after HI. In conclusion, targeting the α7nAChR in neonatal brain injury shows some effect on dampening acute inflammatory responses in male pups. However, this does not lead to an effect on overall injury outcome.

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“…Reverse transcription was performed using the QuantiTect Reverse Transcription Kit (Qiagen GmbH, Hilden, Germany) according to the manufacturer's protocol. The expression of the CHRNA7 and the CHRFAM7A were determined with droplet digital PCR (ddPCR) utilizing EvaGreen (Bio‐Rad Laboratories, CA, USA) as previously described 44 . In short, the T100 Thermal Cycler (Bio‐Rad Laboratories, Hercules, CA, U.S.A.) was used with following settings: 95°C for 5 min, 40 cycles of 96°C for 30 s and 58.8°C for 1 min, 4°C for 5 min followed by 90°C for 5 min.…”

Section: Methodsmentioning

confidence: 99%

“…The expression of the CHRNA7 and the CHRFAM7A were determined with droplet digital PCR (ddPCR) utilizing EvaGreen (Bio-Rad Laboratories, CA, USA) as previously described. 44 In short, the T100 Thermal Cycler (Bio-Rad Laboratories, Hercules, CA, U.S.A.) was used with following settings: 95°C for 5 min, 40 cycles of 96°C for 30 s and 58.8°C for 1 min, 4°C for 5 min followed by 90°C for 5 min. A ramp rate of 2°C/s was used for all steps.…”

Section: Droplet Digital Pcr (Ddpcr)mentioning

confidence: 99%

Polymorphisms in alpha 7 nicotinic acetylcholine receptor gene, CHRNA7 , and its partially duplicated gene, CHRFAM7A , associate with increased inflammatory response in human peripheral mononuclear cells

et al. 2022

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The vagus nerve can, via the alpha 7 nicotinic acetylcholine receptor (α7nAChR), regulate inflammation. The gene coding for the α7nAChR, CHRNA7, can be partially duplicated, that is, CHRFAM7A, which is reported to impair the anti‐inflammatory effect mediated via the α7nAChR. Several single nucleotide polymorphisms (SNPs) have been described in both CHRNA7 and CHRFAM7A, however, the functional role of these SNPs for immune responses remains to be investigated. In the current study, we set out to investigate whether genetic variants of CHRNA7 and CHRFAM7A can influence immune responses. By investigating data available from the Swedish SciLifeLab SCAPIS Wellness Profiling (S3WP) study, in combination with droplet digital PCR and freshly isolated PBMCs from the S3WP participants, challenged with lipopolysaccharide (LPS), we show that CHRNA7 and CHRFAM7A are expressed in human PBMCs, with approximately four times higher expression of CHRFAM7A compared with CHRNA7. One SNP in CHRFAM7A, rs34007223, is positively associated with hsCRP in healthy individuals. Furthermore, gene ontology (GO)‐terms analysis of plasma proteins associated with gene expression of CHRNA7 and CHRFAM7A demonstrated an involvement for these genes in immune responses. This was further supported by in vitro data showing that several SNPs in both CHRNA7 and CHRFAM7A are significantly associated with cytokine response. In conclusion, genetic variants of CHRNA7 and CHRFAM7A alters cytokine responses. Furthermore, given that CHRFAM7A SNP rs34007223 is associated with inflammatory marker hsCRP in healthy individuals suggests that CHRFAM7A may have a more pronounced role in regulating inflammatory processes in humans than previously been recognized.

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The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia–reperfusion brain injury in mice

Cited by 4 publications

References 58 publications

Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

Precision targeting of the vagal anti-inflammatory pathway attenuates the systemic inflammatory response to burn injury

The Alpha 7 Nicotinic Acetylcholine Receptor Does Not Affect Neonatal Brain Injury

Polymorphisms in alpha 7 nicotinic acetylcholine receptor gene, CHRNA7 , and its partially duplicated gene, CHRFAM7A , associate with increased inflammatory response in human peripheral mononuclear cells

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