Effect of Reserpine on the Behavioral Defects, Aβ-42 Deposition and NGF Metabolism in Tg2576 Transgenic Mouse Model for Alzheimer's Disease

Abstract

Reserpine, an anti-hypertensive drug, is able to positively modulate several phenotypes associated with Aβ toxicity in a Caenorhabditis elegans model of Alzheimer's disease (AD). We investigated into the therapeutic effects of reserpine on mammalian neurodegenerative disorders, and found that significant alteration of the key factors influencing AD was detected in Tg2576 mice after reserpine treatment for 30 days. The aggressive behavior of Tg2576 mice was significantly improved upon reserpine treatment, whereas their social contact was consistently maintained. Furthermore, the levels of Aβ-42 peptide in the hippocampus of the brain and blood serum were lower in the reserpine-treated group than in the vehicle-treated group. Among g-secretase components, the expression levels of PS-2, Pen-2, and APH-1 were slightly lower in reserpine-treated Tg2576 mice, although a significant change in nicastrin (NCT) expression was not detected. Furthermore, the serum level of nerve growth factor (NGF) increased in reserpine-treated Tg2576 mice compared with vehicle-treated mice. Among down-stream effectors of the NGF receptor TrkA signaling pathway, reserpine treatment induced elevation of TrkA phosphorylation and reduction of ERK phosphorylation. In addition, in the NGF receptor p75 NTR signaling pathway, the expression levels of p75 NTR and Bcl-2 were enhanced in reserpine-treated Tg2576 mice compared with vehicle-treated mice, whereas the expression level of RhoA declined. Overall, these results suggest that reserpine can help relieve AD pathogenesis in Tg2576 mice through downregulation of Aβ-42 deposition, alteration of γ-secretase components, and regulation of NGF metabolism.

Reserpine Improves Working Memory

“…More importantly, reserpine improved the cognition of the 5xFAD AD Tg mice at the age (Figure 1) where these mice are reported to show cognitive deficits. While our study was ongoing, Go et al [16] reported that reserpine can help relieve AD pathogenesis in Tg2576 mice through down regulation of Aβ 42 deposition, NGF secretion [16], but had not assessed cognitive function. Since decline in cognition is the most devastating feature of AD, here, we show that reserpine improves spatial working memory and delays cognitive deficits in the 5XFAD AD Tg mice at the low dosage of 0.08 mg that too administered only on alternate days which is in line with the low dosage of reserpine currently in use.…”

“…As reserpine modulates biogenic amines neurotransmitters, the secondary problems mentioned above also could be alleviated by it. Go et al [16], report that reserpine can significantly reduce the aggressive behavior in the Tg2576 AD mice. In Ayurvedic medicine, reserpine has been used as an antipsychotic and tranquilizer for more than a millennium.…”

“…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].…”

“…In addition, reserpine ameliorates Aβ-induced toxicity manifested as progressive paralysis, confered stress tolerance and enhanced locomotion till late age in the C. elegans model [15]. The AD mouse model, Tg2576, expresses human mutant APP, which causes Aβ aggregates formation and cognitive deficits at ~11 months of age [16]. In these Tg2576 mice, reserpine reduced Aβ 42 deposits and levels in hippocampus and serum [16].…”

“…The AD mouse model, Tg2576, expresses human mutant APP, which causes Aβ aggregates formation and cognitive deficits at ~11 months of age [16]. In these Tg2576 mice, reserpine reduced Aβ 42 deposits and levels in hippocampus and serum [16]. But reserpine's effect on the major problem of AD, namely, cognitive deficit-progressive dementia or memory loss was not addressed.…”