PNU 282987

PNU-282987 is a selective α7 nicotinic acetylcholine receptor(α7 nAChR) agonist with Ki of 26 nM; no affinity for α1β1γδ and α3β4 nAChRs (IC50 ≥ 60 μM). IC50 value: 26 nM(Ki) [1] Target: α7 nAChR agonist in vitro: Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion [3]. in vivo: Mice were subjected to 70% partial hepatic I/R for 60 min and pretreated with either vehicle or with PNU-282987, and blood and hepatic tissue samples were collected at 3, 6, and 12 h following reperfusion. pretreatment with PNU-282987 decreased serum transaminase levels and ameliorated liver injury after hepatic I/R. Moreover, pretreatment with PNU-282987 suppressed NF-κB activation, cytokine production (tumor necrosis factor α, interleukin 1β), and HMGB1 expression in liver after hepatic I/R [2]. Mice treated with 2.5 and 10 mg/kg of PNU devoted less time to rearing into open arms. In the HB task, MC mice displayed higher exploratory activity reflected in more head-dips (HD) during the first minute than EE and SE, whereas EE displayed low exploration levels reflected in total HD (5 min) [4].

References:
[1]. Bodnar AL, et al. Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors. J Med Chem. 2005 Feb 24;48(4):905-8. [2]. Li F, et al. The protective effect of PNU-282987, a selective α7 nicotinic acetylcholine receptor agonist, on the hepatic ischemia-reperfusion injury is associated with the inhibition of high-mobility group box 1 protein expression and nuclear factor κB activation in mice. Shock. 2013 Feb;39(2):197-203. [3]. Stuckenholz V, et al. The α7 nAChR agonist PNU-282987 reduces inflammation and MPTP-induced nigral dopaminergic cell loss in mice. J Parkinsons Dis. 2013;3(2):161-72. [4]. Mesa-Gresa P, et al. Behavioral effects of different enriched environments in mice treated with the cholinergic agonist PNU-282987. Behav Processes. 2014 Mar;103:117-24. [5]. Dong Jun Yu, et al. Effect of ischemic preconditioning combined with α7 nAchR agonists on limb ischemia-reperfusion lung injury in rat. Biomed Res. 2017; Special Issue: ISSN 0970.

Alpha7 Nicotine Acetylcholine Receptor Agonist PNU-282987 Attenuates Acute Lung Injury in a Cardiopulmonary Bypass Model in Rats.[Pubmed:27661000]

Shock. 2017 Apr;47(4):474-479.

OBJECTIVE: Cardiopulmonary bypass (CPB) carries a risk of lung ischemia-reperfusion, leading to acute lung injury (ALI). Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) has been implicated in the release of high mobility group box1 (HMGB1), which promotes systemic inflammation in response to ischemia-reperfusion injury. However, the specific role of alpha7nAChR in CPB is poorly understood. This study employed the alpha7nAChR agonist PNU-282987 and a rat model of CPB to determine whether alpha7nAChR was associated with CPB-induced lung damage. METHODS: Thirty Sprague-Dawley rats were randomly divided into five groups as follows: normal group, sham group, CPB group, PNU-282987 plus CPB group, and PNU-282987 plus sham group. Rats were subjected to CPB under anesthesia for 60 min. PNU-282987 (4.8 mg/kg) was administered via arterial inflow. Two hours post-CPB, samples of blood, bronchoalveolar lavage fluid (BALF), and lung tissues were processed for investigations. RESULTS: In CPB rats, structural damage in the lung was marked. Density of alpha7nAChR of the lung in the CPB group was significantly less than all other groups, while lung edema, inflammatory markers in serum and lung, protein concentrations in BALF were significantly higher. In the PNU-282987 plus CPB group, by all the above measures the CPB-associated effects were significantly ameliorated but were not identical to the control groups. CONCLUSION: Our results suggest that PNU-282987 affords protective effect against CPB-induced ALI, and inhibits HMGB1 release.

Acute lung injury is reduced by the alpha7nAChR agonist PNU-282987 through changes in the macrophage profile.[Pubmed:27729414]

FASEB J. 2017 Jan;31(1):320-332.

Nicotinic alpha-7 acetylcholine receptor (nAChRalpha7) is a critical regulator of cholinergic anti-inflammatory actions in several diseases, including acute respiratory distress syndrome (ARDS). Given the potential importance of alpha7nAChR as a therapeutic target, we evaluated whether PNU-282987, an alpha7nAChR agonist, is effective in protecting the lung against inflammation. We performed intratracheal instillation of LPS to generate acute lung injury (ALI) in C57BL/6 mice. PNU-282987 treatment, either before or after ALI induction, reduced neutrophil recruitment and IL-1beta, TNF-alpha, IL-6, keratinocyte chemoattractant (KC), and IL-10 cytokine levels in the bronchoalveolar lavage fluid (P < 0.05). In addition, lung NF-kappaB phosphorylation decreased, along with collagen fiber deposition and the number of matrix metalloproteinase-9(+) and -2(+) cells, whereas the number of tissue inhibitor of metalloproteinase-1(+) cells increased (P < 0.05). PNU-282987 treatment also reduced lung mRNA levels and the frequency of M1 macrophages, whereas cells expressing the M2-related markers CD206 and IL-10 increased, suggesting changes in the macrophage profile. Finally, PNU-282987 improved lung function in LPS-treated animals. The collective results suggest that PNU-282987, an agonist of alpha7nAChR, reduces LPS-induced experimental ALI, thus supporting the notion that drugs that act on alpha7nAChRs should be explored for ARDS treatment in humans.-Pinheiro, N. M., Santana, F. P. R., Almeida, R. R., Guerreiro, M., Martins, M. A., Caperuto, L. C., Camara, N. O. S., Wensing, L. A., Prado, V. F., Tiberio, I. F. L. C., Prado, M. A. M., Prado, C. M. Acute lung injury is reduced by the alpha7nAChR agonist PNU-282987 through changes in the macrophage profile.

Behavioral effects of different enriched environments in mice treated with the cholinergic agonist PNU-282987.[Pubmed:24321613]

Behav Processes. 2014 Mar;103:117-24.

Environmental enrichment is an experimental model in which rodents are housed in complex environments that favor lower levels of anxiety-like behavior. PNU-282987 (PNU) is a alpha7 nicotinic acetylcholine receptor agonist with beneficial effects on learning though its effects on anxiety are unclear. Our main aim was to carry out a study of its effects in NMRI (n=96) mice reared in different environments: environmental enrichment (EE), Marlau cages (MC) and standard environment (SE). After a 4-month period, mice received acute treatment of PNU (2.5, 5 and 10mg/kg) and were evaluated in the elevated plus-maze (EPM) and hole-board (HB). In the EPM, both EE and MC reared mice showed an increase in percentage of entries into open arms while those from EE group differed from SE in time spent on open arms. Mice treated with 2.5 and 10 mg/kg of PNU devoted less time to rearing into open arms. In the HB task, MC mice displayed higher exploratory activity reflected in more head-dips (HD) during the first minute than EE and SE, whereas EE displayed low exploration levels reflected in total HD (5 min). Further research is needed in order to clarify the behavioral effects of this nicotinic agonist in interaction with different environmental conditions. This article is part of a Special Issue entitled: insert SI title.

Behavioural effects of PNU-282987 and stress in an animal model of Alzheimer's disease.[Pubmed:26817787]

Psychogeriatrics. 2017 Jan;17(1):33-42.

BACKGROUND: Cholinergic deficits play an important role in both cognitive and behavioural alterations in Alzheimer's disease. This study was aimed at evaluating the possible therapeutic role of PNU-282987 (PNU), an alpha7 nicotinic cholinergic receptor agonist, and the possible effects of stress in precipitating the onset of behavioural deficits in animals with susceptibility to Alzheimer's disease. METHODS: B6C3-Tg mice with susceptibility to Alzheimer's disease and wild-type mice either with or without restraint stress received 0- or 1-mg/kg PNU. At 12 months old, mice were evaluated for activity levels, anxiety-like levels, and spatial learning and memory. RESULTS: Data did not show the effects of PNU on activity and anxiety-like behaviour. No effect of PNU on acquisition of a spatial learning task was detected, but a reversal of stress effects on retention in the Morris water maze was observed in transgenic mice. CONCLUSIONS: Further studies are needed in order to better understand the role of alpha7 nicotinic cholinergic receptor agonists in motor activity, anxiety, and spatial learning and memory and to develop more accurate pharmacological treatment of psychopathological diseases.

PNU-282987 is a selective α7 nicotinic acetylcholine receptor(α7 nAChR) agonist with Ki of 26 nM; no affinity for α1β1γδ and α3β4 nAChRs (IC50 ≥ 60 μM).

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