Major Depressive Disorder is one of the most common chronic mental disorders and a leading cause of disability globally. Recent research indicates that chronic stress exposure is one of the disease's most significant risk factors. Despite the availability of both pharmacological and non-pharmacological therapies, many people with depression remains treatment resistant. Clinical and preclinical investigations have been conducted in recent years with the goal of developing novel medications capable of overcoming these restrictions and to search new pathway that are linked to the disease. The use of animal models has been critical in this context to help the identification of molecular mechanisms that are associated with the disease. In particular, recent data revealed that the ERK-MAP kinase pathway may have a key role in neuropsychiatric illnesses. This study attempted to determinate whether RB5, a cell permeable peptide acting as positive modulator of ERK2, could successfully reverse a depressive like behavior phenotype induced in an animal model of depression (Chronic Restraint Stress, CRS) and to evaluate the possible molecular mechanisms involved. First, we conducted a dose-finding study, subjecting a first set of C57BL/6 naïve mice to intraperitoneal (i.p.) injections every day for seven days with 10 mg/kg or 20 mg/kg RB5. Then, 3 weeks of CRS protocol were applied to a second set of C57BL/6 mice and, after two weeks of stress, mice were i.p. injected every day for one week with 20 mg/kg RB5 (as selected based on the results obtained in the first experiment). In this second set, a separate group of CRS mice was injected with an acute dose of ketamine 10 mg/kg as a positive control for the antidepressant effect. Both drugs reduced the immobility time in forced swim and tail suspension tests, as well as increased the number of groomings in the splash test. Chronic administration of RB5 peptide also restored to basal levels mGluR2 expression upregulated in CRS mice, suggesting a possible involvement of mGluR2 in RB5 antidepressant action. Overall, our results show that RB5 treatment in dose 20 mg/kg for 7 days induced antidepressant effects in rodents.
Il disturbo depressivo maggiore è uno dei disturbi mentali cronici più comuni e una delle principali cause di disabilità a livello globale. Ricerche recenti indicano che l'esposizione allo stress cronico è uno dei fattori di rischio più significativi della malattia. Nonostante la disponibilità di terapie sia farmacologiche che non farmacologiche, molte persone con depressione rimangono resistenti al trattamento. Negli ultimi anni sono state condotte indagini cliniche e precliniche con l'obiettivo di sviluppare nuovi farmaci in grado di superare queste restrizioni e di cercare nuovi pathway legati alla malattia. L'uso di modelli animali è stato fondamentale in questo contesto per aiutare l'identificazione dei meccanismi molecolari associati alla malattia. In particolare, dati recenti hanno rivelato che il pathway di ERK-MAP chinasi può avere un ruolo chiave nelle malattie neuropsichiatriche. Questo studio ha tentato di determinare se RB5, un peptide permeabile alle cellule che funge da modulatore positivo di ERK2, potesse invertire con successo un fenotipo di comportamento depressivo indotto in un modello animale di depressione (Chronic Restraint Stress, CRS) e di valutare i possibili meccanismi molecolari coinvolti. Innanzitutto, abbiamo condotto uno studio di determinazione della dose, sottoponendo un primo gruppo di topi naïve C57BL/6 a iniezioni intraperitoneali ogni giorno per sette giorni con 10 mg/kg o 20 mg/kg di RB5. Successivamente, 3 settimane di protocollo CRS sono state applicate a un secondo set di topi C57BL/6 e, dopo due settimane di stress, i topi sono stati sottoposti a iniezioni intraperitoneali ogni giorno per una settimana con 20 mg/kg di RB5 (come selezionato sulla base dei risultati ottenuti nel primo esperimento). In questo secondo set, a un gruppo separato di topi CRS è stata iniettata una dose acuta di ketamina di 10 mg/kg come controllo positivo per il suo effetto antidepressivo. Entrambi i farmaci hanno ridotto il tempo di immobilità nei test di nuoto forzato e sospensione della coda, oltre ad aumentare il numero di toelettature nello splash test. La somministrazione cronica del peptide RB5 ha anche riportato a livelli basali l'espressione di mGluR2 che era sovraregolata nei topi CRS, suggerendo un possibile coinvolgimento di mGluR2 nell'azione antidepressiva di RB5. Complessivamente, i nostri risultati mostrano che il trattamento con RB5 alla dose di 20 mg/kg per 7 giorni ha indotto effetti antidepressivi nei roditori.
Study of antidepressant properties of the RB5 peptide, a positive modulator of ERK2, in mouse models
PAVESI, MARTINA
2021/2022
Abstract
Major Depressive Disorder is one of the most common chronic mental disorders and a leading cause of disability globally. Recent research indicates that chronic stress exposure is one of the disease's most significant risk factors. Despite the availability of both pharmacological and non-pharmacological therapies, many people with depression remains treatment resistant. Clinical and preclinical investigations have been conducted in recent years with the goal of developing novel medications capable of overcoming these restrictions and to search new pathway that are linked to the disease. The use of animal models has been critical in this context to help the identification of molecular mechanisms that are associated with the disease. In particular, recent data revealed that the ERK-MAP kinase pathway may have a key role in neuropsychiatric illnesses. This study attempted to determinate whether RB5, a cell permeable peptide acting as positive modulator of ERK2, could successfully reverse a depressive like behavior phenotype induced in an animal model of depression (Chronic Restraint Stress, CRS) and to evaluate the possible molecular mechanisms involved. First, we conducted a dose-finding study, subjecting a first set of C57BL/6 naïve mice to intraperitoneal (i.p.) injections every day for seven days with 10 mg/kg or 20 mg/kg RB5. Then, 3 weeks of CRS protocol were applied to a second set of C57BL/6 mice and, after two weeks of stress, mice were i.p. injected every day for one week with 20 mg/kg RB5 (as selected based on the results obtained in the first experiment). In this second set, a separate group of CRS mice was injected with an acute dose of ketamine 10 mg/kg as a positive control for the antidepressant effect. Both drugs reduced the immobility time in forced swim and tail suspension tests, as well as increased the number of groomings in the splash test. Chronic administration of RB5 peptide also restored to basal levels mGluR2 expression upregulated in CRS mice, suggesting a possible involvement of mGluR2 in RB5 antidepressant action. Overall, our results show that RB5 treatment in dose 20 mg/kg for 7 days induced antidepressant effects in rodents.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/15878