Neurochemical Effects of the Adipokinetic Hormone/Red Pigment Concentrating Hormone Family of Peptides in MK-801-Induced Schizophrenia Rat Model

Abstract

Objective: Adipokinetic hormone (AKH) plays a role in sugar and lipid metabolism in insects. Previous studies of AKH showed memory improvements in a schizophrenia rat model that displayed memory impairment and reduced depression in a rat olfactory bulbectomy model. In this study, we investigated the effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on brain neurotransmitter levels and brain neurochemistry in a schizophrenia rat model. Materials and Methods: We administered AKH/RPCH peptides for 4 days sub-chronically, both in naive rats and also in the MK-801-induced schizophrenia rat model. Liquid chromatography-mass spectrometry apparatus was used for targeted and untargeted analysis of rat neurochemistry. Results: Increased brain glutamate levels characteristic of MK-801 peptide-treated rats were significantly reduced by AKH. Furthermore, AKH also increased brain dopamine levels in both naive and MK-801 rats. Metabolomic studies have shown that AKH affects lipid and glutamate metabolism, while hypertrehalosaemic hormone plays a role in sugar metabolism and inflammation. Conclusion: According to our results, AKH might affect dopaminergic and glutamatergic systems and reverse the effects of MK-801, possibly affecting NMDA receptors.

Keywords

• Adipokinetic hormone
• neurochemistry
• neurotransmitters
• schizophrenia

Adipokinetik Hormon/Kırmızı Pigment Konsantre Hormon Peptid Ailesinin MK-801'in İndüklediği Şizofreni Sıçan Modelinde Nörokimyasal Etkileri

Öz

Amaç: Adipokinetik hormon (AKH) böceklerde şeker ve lipid metabolizmasında rol oynar. Önceki çalışmalarda AKH sıçan şizofeni modelinde belleği ve sıçan olfaktör bulbektomi modelinde depresyonu düzelttiği gösterilmiştir. Bu çalışmada, adipokinetik hormon/kırmızı pigment konsantre edici hormon (AKH/RPCH) ailesi peptidlerinin sıçan şizofreni modelinde beyin nörotransmitter seviyesi ve beyin nörokimyası üzerine etkisi araştırılmıştır. Materyal ve Metot: Peptidleri hem naif sıçanlarda hem de MK-801 ile indüklenmiş sıçan şizofreni modelinde 4 gün boyunca subkronik olarak uyguladık. Likid kromatografi-kütle spektrometri cihazı nörokimyanın hedeflenmiş ve hedeflenmemiş analizi için kullanıldı. Bulgular: AKH anlamlı olarak MK-801 uygulanmış sıçanlarda artmış beyin glutamat seviyesini düşürmüştür. AKH ayrıca hem naif sıçanlarda hem MK-801 uygulanmış sıçanlarda beyin dopamin seviyesini artırdı. Metabolomik çalışmalar adipokinetik hormonun lipid ve glutamat metabolizmasını etkilediğini, hipertrehalosemik hormonun ise şeker metabolizması ve enflamasyonda rol oynadığını gösterdi. Sonuç: Sonuçlarımıza göre AKH dopaminerjik ve glutamaterjik sistemi etkileyebilir ve MK-801’in etkilerini muhtemelen NMDA reseptörleri üzerinden tersine çeviriyor olabilir.

Anahtar Kelimeler

• Adipokinetik hormon
• nörokimya
• nörotransmitter
• şizofreni

Kaynakça

1. Gade G, Marco HG. Adipokinetic and hypertrehalosemic neurohormones. Encyclopedia of Entomology. 2008;4:44-45.
2. Gade G. The hormonal integration of insect flight metabolism. Zool Jahrb Physiol. 1992;96:211.
3. Suzuki H, Sato S, Tsuchiya T, et al. Identification and characterization of adipokinetic hormone (Locusta migratoria)-like immunoreactivity in the human cerebrospinal fluid. Biochem Biophys Res Commun. 1989;163(1):534-540. doi:10.1016/0006-291x(89)92170-0
4. Staubli F, Jorgensen TJ, Cazzamali G, et al. Molecular identification of the insect adipokinetic hormone receptors. Proc Natl Acad Sci USA. 2002;99(6):3446-3451. doi:10.1073/pnas.052556499
5. Sasek CA, Schueler PA, Herman WS, Elde RP. An antiserum to locust adipokinetic hormone reveals a novel peptidergic system in the rat central nervous system. Brain Res. 1985;343(1):172-175. doi:10.1016/0006-8993(85)91173-4
6. Mutlu O, Gumuslu E, Kokturk S, et al. Effects of chronic administration of adipokinetic and hypertrehalosemic hormone on animal behavior, BDNF and CREB expression in the hippocampus and neurogenesis in mice. Fundam Clin Pharmacol. 2016;30(1):4-13. doi:10.1111/fcp.12165
7. Mutlu O, Ulak G, Akar F, et al. Effects of acute administration of adipokinetic hormone on depression, anxiety, pain, locomotion and memory in mice. Chin J Physiology. 2017;60(2):106-113. doi:10.4077/CJP.2017.BAF450
8. Mutlu O, Páleníček T, Pinterová N, et al. Effects of the adipokinetic hormone/red pigment-concentrating hormone (AKH/RPCH) family of peptides on MK-801-induced schizophrenia models. Fundam Clin Pharmacol. 2018;32(6):589-602. doi:10.1111/fcp.12386

9. Mutlu O, Kurtas O, Kleteckova L, et al. Effects of adipokinetic hormone/red pigment-concentrating hormone family of peptides in olfactory bulbectomy model and posttraumatic stress disorder model of rats. Peptides. 2020. doi:10.1016/j.peptides.2020.170408
10. Brisch R, Saniotis A, Wolf R, et al. The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue. Front Psychiatry. 2014;5:47. doi:10.3389/fpsyt.2014.00047
11. Mutlu O, Tanyeri P, Basarir S, et al. Effects of Pyroglutamyl Peptides on Depression, Anxiety and Analgesia in Mice. IJMRHS. 2021;10(5):56-62.
12. Zhou X, Cai G, Mao S, et al. Modulating NMDA receptors to treat MK-801-induced schizophrenic cognition deficit: effects of clozapine combining with PQQ treatment and possible mechanisms of action. BMC Psychiatry. 2020;20:106. doi:10.1186/s12888-020-02509-z