Latrepirdine (dihydrochloride)

97657-92-6

C21H27Cl2N3

DMSO : 6.4 mg/mL (16.31 mM; Need warming)

Neuronal Signaling; Immunology/Inflammation; GPCR/G Protein; GPCR/G Protein; Autophagy; Neuronal Signaling; GPCR/G Protein; Neuronal Signaling; Neuronal Signaling

Latrepirdine dihydrochloride is a neuroactive compound with antagonist activity at histaminergic, alpha-adrenergic, and serotonergic receptors. Latrepirdine stimulates amyloid precursor protein (APP) catabolism and amyloid-beta (Abeta) secretion. IC50 & Target: Amyloid-beta (Abeta), Histaminergic receptor, alpha-adrenergic receptor, Serotonergic receptor^[1] In Vitro: Latrepirdine has been reported to possess several properties that are potentially relevant to the treatment of neurodegenerative diseases: (1) protection of cultured cells from the cytotoxicity of amyloid-beta (Abeta) peptide; (2) stabilization of mitochondrial function and calcium homeostasis; (3) modulation of Abeta release from cultured cells, isolated intact nerve terminals, and from hippocampal neurons in living mouse brain; and (4) promotion of neurogenesis in the murine hippocampus. Treatment of cultured mammalian cells with Latrepirdine leads to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine modulates Atg5-dependent autophagic activity in a dose-dependent manner and via the mTOR-signaling pathway. HeLa cells stably expressing LC3 fused are treated with EGFP (eGFP-LC3) for 3 or 6 hours in the absence or presence of 50 uM Latrepirdine. Treatment with Latrepirdine for 3 or 6 hours markedly enhances the number of eGFP-LC3 punctae, indicating that Latrepirdine induces formation of autophagosomes. Next, mouse N2a neuroblastoma cells are treated in the absence (vehicle) or presence of 5 nM, 500 nM or 50 uM Latrepirdine for 3 or 6 hours in order to determine the effects of acute drug treatment on the regulation of autophagy. A significant and dose-dependent increase is observed in LC3-II levels in N2a cells following 3- or 6-hour treatment with either 500 nM or 50 uM Latrepirdine. A significant decrease of p-mTOR and p-S6K from N2a cells treated with 50 uM Latrepirdine for 3 hours is observed, whereas the total mTOR and p70S6K levels remain relatively constant^[1]. In Vivo: Latrepirdine treatment of TgCRND8 transgenic mice is associated with improved learning behavior and with a reduction in accumulation of Abeta42 and alpha-synuclein. Male, 90-day-old TgCRND8 mice or their wild-type littermates (nTg) receive 31 consecutive once daily i.p. injections of either 3.5 mg/kg Latrepirdine or 0.9% saline (vehicle). At the culmination of treatment, mice are tested for cued and contextual fear conditioning using a paradigm that has been widely accepted for evaluating learning and memory deficits in APP transgenic mice. A significant increase in cued memory only among Latrepirdine-versus vehicle-treated TgCRND8 mice (p=0.01) is observed. A weak, non-significant trend toward an improvement in contextual memory among Latrepirdine-versus vehicle-treated mice (p=0.099) is also observed^[1].