RESUMO
Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimer's disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE in vitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23 µM. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16 µM, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues.
Assuntos
Inibidores da Colinesterase , Glicosídeos/química , Lignanas/química , Lycopodiaceae/química , Simulação de Acoplamento Molecular , Extratos Vegetais , Água/química , Ligação Competitiva , Bioensaio , Fracionamento Químico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Glicosídeos/farmacologia , Humanos , Concentração Inibidora 50 , Cinética , Lignanas/farmacologia , Metanol/química , Modelos Moleculares , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ligação ProteicaRESUMO
A series of Lycopodium alkaloids, namely lycosquarosine A (1), acetylaposerratinine (2), huperzine A (3), huperzine B (4), 8α-hydrophlemariurine B (5), and huperzinine (6), has been isolated from Vietnamese Huperzia squarrosa. Among them, lycosquarosine A (1) is the new metabolite of the natural source. Lycosquarosine A completely inhibited AChE activity in a dose dependent manner with an IC50 value of 54.3 µg/mL, while acetylaposerratinine (2) showed stronger inhibitory activity than 1 with an IC50 value of 15.2 µg/mL. This result indicates that these alkaloids may be a potent source of AChE inhibitors.
Assuntos
Alcaloides/química , Alcaloides/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Huperzia/química , Lycopodium/química , Concentração Inibidora 50 , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
Lycopodiella cernua (L.) Pic. Serm. (Licopodiaceae) has been used in Vietnamese folk medicine for treating central nervous system conditions. In this study, the alkaloid fraction from the methanol extract of this plant (VLC) was evaluated for in vitro acetylcholinesterase (AChE) inhibitory activity in cognition-relevant brain areas of mice. In in vivo study, the cognitive-enhancing effect of VLC on amnesic mice induced by scopolamine was investigated by assessing a passive avoidance and a Morris water maze test. VLC inhibited AChE activity in mouse frontal cortex, hippocampus and striatum with IC50 values of 26.7, 32.2 and 25.7µg/mL, respectively. Administration of VLC (10, 20, 50 and 100mg/kg, p.o.) significantly reversed cognitive impairments in mice by passive avoidance test. Treating with VLC (50mg/kg) reduced escape latencies in training trials and prolonged swimming times in the target quadrant during the probe trial in the water maze task (P<0.05). These results indicated that L. cernua originated from Vietnam has anti-cholinesterase activity and might be useful for the treatment of cognitive impairment.