Altered expression of γ-secretase components in animal model of major depressive disorder induced by reserpine administration

Abstract

Altered expression of neurotrophic factors as well as neuroinflammation is commonly associated with Major depressive disorder (MDD) and Alzheimer's disease (AD). To investigate whether or not reserpine-induced MDD affects the expression of AD-related proteins, the expression of γ-secretase components and substrate were measured in brains of ICR mice following reserpine treatment for 15 days. In active avoidance test, total response time and peak slightly increased in the 2 mg/kg reserpine (RSP2)-treated group compared to vehicle-treated group (P<0.05). Expression and phosphorylation of MKP-1, which is a key factor in MDD pathology, were both higher in the RSP2-treated group than the vehicle- and 1 mg/kg reserpine (RSP1)-treated groups (P<0.02). Furthermore, full-length expression of amyloid precursor protein (APP) was enhanced in the RSP1 and RSP2-treated groups compared to the vehicle-treated group, whereas expression of γ-secretase components decreased (P<0.03). Among the three components of the γ-secretase complex, nicastrin protein underwent the largest decrease in expression, as detected by Western blotting (P<0.03). Therefore, the data presented here provide additional evidence about the pathological correlation between MDD and AD.

Behavioral effects of bidirectional modulators of brain monoamines reserpine and d-amphetamine in zebrafish

“…In humans, this agent generally induces antipsychotic, calming (tranquilizing) and pro-depressant effects (Quetsch et al 1959; Freis 1954; Baumeister et al 2003; Estes 1995; Bigelow 2006; Yaniv and Bachrach 2005). In rodents, reserpine causes hypoactivity (Williams and Pirch 1974), motor stereotypies (Neisewander et al 1991), akinesia (Dolphin et al 1976), lethargy (Sigg et al 1965) and anhedonia (Skalisz et al 2002), relevant to depression (Borison et al 1978; Lee et al 2012) and Parkinson’s disease (PD) (Duty and Jenner 2011). The drug also exerts conflicting action on clinical (Shamon and Perez 2009; Sarwer-Foner and Ogle 1956; Starkweather 1959) and animal anxiety, including no effects (Angrini et al 1998; Heslop and Curzon 1999), increased (Angrini et al 1998; Heslop and Curzon 1999; Haggendal and Lindqvist 1963; Ahlenius and Salmi 1994; LaBuda and Fuchs 2002) or reduced anxiety (Xu et al 1992) (also see tranquilizing effects is some fish species (Turner and Carl 1955; Cano 1959)).…”

Reserpine Improves Working Memory

“…Reserpine has a strong potential to be a candidate drug for AD, because: 1) first and foremost, it improves working memory (Figure 1 and Figure 2); 2) it decreases Aβ 42-deposits/levels in brain and serum [16]; 3) it increases NGF secretion and its action through TrkA signaling [16]; 4) it induces expression of antiapoptotic protein, BCL-2 which can protect against neuronal loss [16]; 5) it does not inhibit or drastically downregulate the gamma-secretase complex [16] which is crucial for notch signaling, lack of which leads to cancer [3] [4]; 6) it can cross the blood brain barrier; 7) the major caveat about reserpine is the development of depression, and at a low dosage of 1 mg/kg reserpine does not cause depression in mice and the maniac depression pathological marker mkb-1 is not induced [19], but at the dosage of 2 mg/kg both these effects are noticed [19]; 8) it is widely in use, especially as an antihypertensive drug, even as a community based prophylactic at the low dosage of 0.05 mg against hypertension with minimal side effects for several years [13] [20]; 9) it reduces mortality when used as an antihypertensive [17].…”

Molecular Mechanisms and Applications of a Reserpine-Induced Rodent Model

“…Mohammed [39] Alzheimer's and Major Depressive Disorder Pathology Promotion of inflammatory response leading to malformed proteins involved with Alzheimer's Disease Lee et al [26] Depression-Pain Dyad…”

“…Vilpoux et al [19] , Urigüen et al [20] , Lee et al [23] , Lee et al [26] Irritable Bowel Syndrome Model Developing an IBS model that relies on the addition of the depression exhibited in patients suffering from IBS to study its pathogenesis and treatment…”

“…Alterations of gene expression levels for neurotrophic factors and neuronal inflammation have been known in MDD and Alzheimer's disease. The cleavage of the amyloid precursor protein, one of the genetic factors of Alzheimer's disease, was suppressed due to γ-secretase expression that was inhibited by Reserpine-induced-MDD in mice [26] . The Reserpine animal model of depression has been shown to have additive effects for the severity of inflammatory bowel disease (IBD) models, as the concentrations of key inflammatory proteins like IL-1β, TNF, and IL-6 were elevated in the IBD-induced rodents, including an increase in severity of their inflammation [27,28] .…”