RESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-ß peptide (Aß) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aß neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aß were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aß peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Floroglucinol/análogos & derivados , Presenilina-1/genética , Processamento de Proteína Pós-Traducional , Transmissão Sináptica/genética , Terpenos/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Floroglucinol/administração & dosagem , Floroglucinol/farmacologia , Processamento de Proteína Pós-Traducional/genética , Transmissão Sináptica/efeitos dos fármacos , Terpenos/administração & dosagemRESUMO
St. John's Wort (SJW) has been used medicinally for over 5,000 years. Relatively recently, one of its phloroglucinol derivatives, hyperforin, has emerged as a compound of interest. Hyperforin first gained attention as the constituent of SJW responsible for its antidepressant effects. Since then, several of its neurobiological effects have been described, including neurotransmitter re-uptake inhibition, the ability to increase intracellular sodium and calcium levels, canonical transient receptor potential 6 (TRPC6) activation, N-methyl-D-aspartic acid (NMDA) receptor antagonism as well as antioxidant and anti-inflammatory properties. Until recently, its pharmacological actions outside of depression had not been investigated. However, hyperforin has been shown to have cognitive enhancing and memory facilitating properties. Importantly, it has been shown to have neuroprotective effects against Alzheimer's disease (AD) neuropathology, including the ability to disassemble amyloid-beta (Abeta) aggregates in vitro, decrease astrogliosis and microglia activation, as well as improve spatial memory in vivo. This review will examine some of the early studies involving hyperforin and its effects in the central nervous system (CNS), with an emphasis on its potential use in AD therapy. With further investigation, hyperforin could emerge to be a likely therapeutical candidate in the treatment of this disease.
