PNU-120596 (NSC 216666 ) is a potent and selective positive allosteric α7 nAChR modulator with an EC50 of 0.2 μM. PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons[3]. PNU-120596 enhanced voltage-dependent inhibition of α(7) responses by bicuculline and choline. In the presence of PNU-120596, α(7) channels favored a burst-like kinetic modality in the presence, but not absence of bicuculline and bursts of α(7) openings were voltage-dependent[4]. The PNU 120596 (1 or 4 mg/kg, i.p.) dose-dependently prevented LPS-induced (lipopolysaccharide) depressive-like behavior during FST, TST, FST (forced swim test), TST (tail suspension test) and sucrose preference test. Similarly, the PNU 120596 (4 mg/kg, i.p.) significantly reduced LPS-induced increased expression of Iba-1 in the hippocampus or prefrontal cortex[5].
PNU-120596 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Hippocampal CA1 interneurons
1 μM
3 h
PNU-120596 did not significantly delay COGD-induced depolarization/injury of hippocampal CA1 interneurons.
Br J Pharmacol. 2013 Aug;169(8):1862-78.
Hippocampal CA1 pyramidal neurons
1 μM
3 h
PNU-120596 significantly delayed anoxic depolarization/injury of hippocampal CA1 pyramidal neurons subjected to COGD.
Br J Pharmacol. 2013 Aug;169(8):1862-78.
human chromaffin cells
10 µM
potentiated the nicotinic current and exocytosis elicited by ACh
Br J Pharmacol. 2012 Feb;165(4):908-21.
Bosc-23 cells
10 µM
To investigate the potentiation of α7 acetylcholine receptor single-channel currents by PNU-120596, results showed that PNU-120596 significantly enhanced the open time of the channels in the presence of calcium.
Cell Mol Life Sci. 2024 Aug 7;81(1):332.
PNU-120596 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Middle cerebral artery occlusion (MCAO) model
Subcutaneous and intravenous
30 mg/kg (s.c.), 1 mg/kg (i.v.)
Single dose, 3 h pre-MCAO and 30 min post-MCAO
PNU-120596 significantly reduced the cortical/subcortical infarct volume when administered 3 h pre-MCAO and 30 min post-MCAO.
Br J Pharmacol. 2013 Aug;169(8):1862-78.
Rats
MCAO model
Intravenous (i.v.) and subcutaneous (s.c.)
2.3 mg/kg (i.v.), 11.1 mg/kg, 5.5 mg/kg
I.v. at 90 minutes, s.c.1 at 5 hours, s.c.2 at 24 hours, s.c.3 at 48 hours, lasting for 72 hours
To test the therapeutic efficacy of PNU-120596 in the MCAO model, results showed that extending treatment duration enhances the therapeutic efficacy of PNU-120596 and reduces relapses
Pharmacol Res. 2018 Oct;136:121-132
Mice
Chronic Intermittent Ethanol model
Intraperitoneal injection
3 or 8 mg/kg
Single dose
To evaluate the effect of PNU-120596 on the Ro 61-8048-induced reduction in ethanol consumption, results showed that PNU-120596 prevented the Ro 61-8048-induced decrease in ethanol consumption and preference.
Br J Pharmacol. 2022 Jul;179(14):3711-3726
Mice
Carrageenan-induced inflammatory pain model and chronic constriction injury (CCI) neuropathic pain model
Intraperitoneal injection
1, 2, 4, 8 mg/kg
Single injection, lasting up to 6 hours
PNU-120596 significantly reduced carrageenan-induced thermal hyperalgesia and edema, and exhibited long-lasting anti-hyperalgesic and anti-allodynic effects in the CCI model.
Neuropharmacology. 2013 Feb;65:156-64
Rats
Young rats and aged cognitively-impaired rats
Intraperitoneal injection
0.1–10 mg/kg
Single administration
To evaluate the effects of PNU-120596 on memory task performance, which was not significant when administered alone but was effective in combination with a subthreshold dose of donepezil.
Neuropharmacology. 2013 Apr;67:201-12
Sprague Dawley rats
Cognitive impairment model
Intraperitoneal injection
3 mg/kg
Twice a week for 5 weeks
PNU-120596 reversed scopolamine-induced cognitive impairment and restored memory function to normal levels.
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