2026 ECNP Congress

EP01-1015

Effects of pyroglutamyl dipeptides on animal behaviour in rats

Emre Uyar — O. Mutlu, M. Chvojkova, K. Holubova, K. Kekrtova, L. Cejkova, P. Çobanturk, G. Ulak, F. Erden, F. Akar, K. Vales · Uskudar University, Medical Pharmacology, İstanbul, Türkiye

2026 ECNP Congress

Objectives

Insect adipokinetic hormones (AKH) play a role in sugar and lipid mobilization and support the production of energy for flight and movement of insects [1]. In our previous studies, we showed that AKH had antidepressant, anxiolytic, and analgesic effects, and that it increased neurotrophic factors and neurogenesis [2,3]. We also showed that AKH improved learning and memory [4]. In our previous study, we hypothesized that metabolites of AKH, including pyroglutamic acid and pyroglutamyl peptides, cross the blood-brain-barrier after intraperitoneal administration of AKH in rats [5]. This hypothesis is also supported by other studies.

Aims

To evaluate the behavioral, cognitive, and anticonvulsant effects of the pyroglutamyl peptides pyroglutamate-valine (pGlu-Val) and pyroglutamate-leucine (pGlu-Leu), alone and combined with MK-801 in rats. We assessed anxiety, social interaction, sensorimotor gating, memory, and pentylenetetrazole-induced seizures.

Methods

Adult male Wistar rats (n ≥ 5 per group) were used. pGlu-Val and pGlu-Leu were dissolved in saline and administered i.p. (0.1, 1, and 3 mg/kg) 30 minutes before testing. Baseline effects were assessed using the negative geotaxis (NG) and elevated plus maze (EPM) tests. Peptides were given alone or together with MK-801 for interaction studies. Behavioral testing were the open field (OF, 0.2 mg/kg MK-801), social preference (SP, 0.2 mg/kg), prepulse inhibition of the acoustic startle response (PPI, 0.3 mg/kg), and the Morris water maze (MWM, 0.1 mg/kg) for working memory. Seizure susceptibility was examined in 25-day-old rats after pentylenetetrazole (100 mg/kg) administrations. The frequency and severity of generalized seizures were recorded.

Results

Dipeptides did not affect motor function in the NG test, also they did not affect open arm time or distance moved in the EPM test. In the OF test, they did not alter total distance moved, MK-801-induced hyperlocomotion, or center time. No effect was observed on the social preference index in the SP test. Dipeptides, in both naive and MK-801-treated rats, did not affect PPI. Dipeptides also had no effect on working memory or distance moved in the MWM test. In the pentylenetetrazole-induced seizure model, pGlu-Val significantly reduced generalized seizure frequency and seizure intensity. In the patch clamp test, there was no significant effect of dipeptides on NMDA receptors.

Discussion

The lack of behavioral effects across multiple paradigms suggests that pGlu-Val and pGlu-Leu do not significantly modulate locomotor, cognitive, or sensorimotor gating functions under these conditions. Also, they do not affect MK-801-induced alterations. But, the reduction in seizure frequency and severity with pGlu-Val in the pentylenetetrazole model points to a selective anticonvulsant profile that appears independent of NMDA receptor modulation.

Conclusions

In conclusion, there was no significant effect of the dipeptides pGlu-Val and pGlu-Leu on the behavior of adult rats, and also on the behavior of MK-801-treated rats at the doses of 0.1, 1, and 3 mg/kg. There was an anticonvulsant effect of pGlu-Val at a dose of 10 mg/kg in the pentylenetetrazole-induced seizure model. In further studies, the behavioral effects of dipeptides at higher doses (at least 10 and 20 mg/kg), and their effects on other glutamatergic receptors and glutamatergic activity should be investigated.

References

  1. Gade, G., Marco, H.G. (2008). Adipokinetic and hypertrehalosemic neurohormones. Encyclopedia of Entomology, 44, 5.
  2. Mutlu, O., Gumuslu, E., Kokturk, S., Ulak, G., Akar, F., Erden, F., Tanyeri, P. (2016). Effects of chronic administration of adipokinetic and hypertrehalosemic hormone on animal behavior, BDNF and CREB expression in the hippocampus and neurogenesis in mice. Fundamental & Clinical Pharmacology, 30, 4-13.
  3. Mutlu, O., Ulak, G., Akar, F., Erden, F., Celikyurt, I. K.., Bektas, E., Kaya, H. (2017). Effects of Acute Administration of Adipokinetic Hormone on Depression, Anxiety, Pain, Locomotion and Memory in Mice. Chinese Journal of Physiology, 60,106-113.
  4. Mutlu, O., Páleníček, T., Pinterová, N., Šíchová, K., Horáček, J., Holubová, K., Valeš, K. (2018). Effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on MK-801-induced schizophrenia models. Fundamental & Clinical Pharmacology,32(6),589-602.
  5. Mutlu, O., Kurtas, O., Kleteckova, L., Pinterova, N., Holubová, K., Horacek, J., Vales, K. (2020). Effects of adipokinetic hormone/red pigment-concentrating hormone family of peptides in olfactory bulbectomy model and posttraumatic stress disorder model of rats. Peptides. Sep 18,134:170408.