Cell lines

Rodent BRIN-BD11 beta-cells

Preparation Method

Cells were incubated (20 min) with JMV 449 alone (1×10^-4-1μM), or in combination with GIP (1×10^-4-1μM) or GLP-1 (1×10^-4-1μM), as well as combination of all three test peptides.

Reaction Conditions

1×10^-4-1μM JMV-449

Applications

JMV 449 displayed significant (P

Animal models

Male C57BL/6 mice, 10 month old

Preparation Method

Cumulative food intake was assessed in overnight fasted (18h) mice following i.p. injection of saline vehicle (0.9% w/v NaCl) or test peptide (JMV 449, (D-Ala²)GIP, and exendin-4), with food intake measured at 30min intervals for 180min.

Dosage form

25nmol/kg

Applications

JMV 449, (D-Ala²)GIP, and exendin-4, induced a significant (P2)GIP and JMV 449, together with 2.5nmol/kg exendin-4, there was a significant reduction (P2)GIP plus exendin-4 injection alone.

JMV 449 is a potent, long-lasting neurotensin receptor agonist^[1,2]. JMV 499 inhibits the binding of¹²⁵I-neurotensin to newborn mouse brain homogenates (IC₅₀=0.15nm), and contracts isolated guinea-pig ileum preparations(EC₅₀=1.9nM)^[3].

JMV 449 induced noticeable dose-dependent insulin releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV 449 augmented(P<0.05) the insulinotropic actions of both hormones, as well as enhancing (P<0.001) insulin secretory activity of both incretin peptides^[4]. JMV 449 induced high affinity neurotensin receptor (NTR) gene activation in the human neuroblastoma cell line CHP212^[5]. JMV 449 (1M) was found to increase tyrosine hydroxylase protein and mRNA abundance after short- and long-term treatments (5 or 72h) in CHP212 cell^[6]

MV 449 (25nmol/kg) inhibited (P<0.05–P<0.001) food intake in overnight fasted lean mice, and enhanced (P<0.01) the appetite suppressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV 449 evoked glucose lowering actions, but more interestingly significantly augmented (P<0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics^[4].JMV 449 induces hypothermia and is able to decrease the infarct size both 24h and 14 days after the onset of permanent focal ischaemia demonstrates its significant neuroprotective potential in mouse model of permanent focal ischaemia^[7]

References:
[1]. Dubuc I, Costentin J, et al. JMV 449: a pseudopeptide analogue of neurotensin-(8-13) with highly potent and long-lasting hypothermic and analgesic effects in the mouse. Eur J Pharmacol. 1992;219(2):327-329.
[2]. Craig SL, Gault VA, et al. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021;1865(8):129917.
[3]. Lugrin D, Vecchini F, et al. Reduced peptide bond pseudopeptide analogues of neurotensin: binding and biological activities, and in vitro metabolic stability. Eur J Pharmacol. 1991;205(2):191-198.
[4]. Irwin N. Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control. Biochim Biophys Acta Gen Subj. 2021;1865(8):129917.
[5]. Najimi M, Souazé F, et al. Activation of receptor gene transcription is required to maintain cell sensitization after agonist exposure. Study on neurotensin receptor. J Biol Chem. 1998;273(34):21634-21641.
[6]. Najimi M, Hermans E, et al. Transcriptional regulation of the tyrosine hydroxylase gene by neurotensin in human neuroblastoma CHP212 cells. Metab Brain Dis. 2001;16(3-4):165-174.
[7]. Torup L, Borsdal J, et al. Neuroprotective effect of the neurotensin analogue JMV-449 in a mouse model of permanent middle cerebral ischaemia. Neurosci Lett. 2003;351(3):173-176.