RESUMEN
Alzheimer's disease (AD) and other forms of dementia represent major public health challenges but effective therapeutic options are limited. Pathological brain aging is associated with microvascular changes and impaired clearance systems. The application of omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) is one of the most promising nutritional interventions in neurodegenerative disorders from epidemiological data, clinical and pre-clinical studies. As essential components of neuronal membranes, n-3 PUFAs have shown neuroprotection and anti-inflammatory effects, as well as modulatory effects through microvascular pathophysiology, amyloid-beta (Aß) clearance and glymphatic pathways. This review meticulously explores these underlying mechanisms that contribute to the beneficial effects of n-3 PUFAs against AD and dementia, synthesizing evidence from both animal and interventional studies.
Asunto(s)
Enfermedad de Alzheimer , Ácidos Grasos Omega-3 , Animales , Barrera Hematoencefálica/metabolismo , Ácidos Grasos Omega-3/farmacología , Ácidos Grasos Omega-3/metabolismo , Encéfalo/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA.
Asunto(s)
Axones/fisiología , Berberina/farmacología , Neuronas Motoras/citología , Regeneración Nerviosa/efectos de los fármacos , Reimplantación/métodos , Traumatismos de la Médula Espinal/prevención & control , Raíces Nerviosas Espinales/cirugía , Animales , Femenino , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/patología , Raíces Nerviosas Espinales/lesiones , Raíces Nerviosas Espinales/patología , Nervios Espinales/trasplanteRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Chrysanthemum indicum Linne (C. indicum), a healthy food and folk medicine in China for thousands of years, has been reported to exert heat-clearing and detoxifying effects and extensively applied to treat various symptoms such as inflammation diseases, hepatitis and headache. AIM OF THIS STUDY: The purpose of the present study was to investigate the protective effect of the supercritical carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) on D-galactose-induced brain and liver damage during aging process and to illuminate the underlying mechanisms. MATERIALS AND METHODS: Mice were orally administrated with CISCFE (100, 150 and 300â¯mg/kg) after injection with D-galactose. 24â¯h after the last administration, the blood samples, whole brain and liver tissues were collected for biochemical analysis, histological examination and western blot analysis. The body weight, spleen and thymus indexes, alanine transaminase (ALT), aspartate transaminase (AST), total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) in brain and liver, interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and necrosis factor-α (TNF-α) were detected. Besides, the expressions of Bax, Bcl-2 and cleaved caspase-3 were determined by western blot assay. RESULTS: The results indicated that CISCFE effectively increased the suppressed body weight, attenuated the decline of thymus and spleen indexes, and reduced the elevated levels of ALT and AST induced by D-gal. Furthermore, CISCFE might notably alleviate D-gal-induced abnormal alterations in structure and function of brain and liver dose-dependently via renewing normal antioxidant enzymes activities (SOD, CAT, GSH-Px), reducing MDA accumulation, decreasing inflammatory cytokines productions (IL-1ß, IL-6, TNF-α), as well as attenuating the increase of Bax/Bcl-2 ratio and cleaved caspase-3 activation in the liver and brain. CONCLUSIONS: Taken together, our present results suggested that CISCFE treatment could effectively mitigate the D-gal-induced hepatic and cerebral injury, and the underlying mechanism might be tightly related to the decreased oxidative stress, inflammation and apoptosis, indicating CISCFE might be an alternative and promising agent for the treatment of aging and age-associated brain and liver diseases.
Asunto(s)
Chrysanthemum/química , Inflamación/prevención & control , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Envejecimiento/patología , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Dióxido de Carbono/química , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Flores , Galactosa/toxicidad , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Extractos Vegetales/administración & dosificación , Superóxido Dismutasa/metabolismoRESUMEN
OBJECTIVE: To assess the cumulative evidence on the efficacy and effectiveness of Ginkgo biloba extract (GbE) in the treatment of dementia. DESIGN: Overview of systematic reviews. METHODS: PubMed/MEDLINE, EMBASE, Cochrane, and Google Scholar were searched in June 2016. Systematic reviews (SRs) of randomized controlled trials (RCTs) evaluating the effects of GbE on different outcomes in people with dementia or cognitive impairment were included. Methodological quality of the included SRs was assessed using the AMSTAR tool. The quality of evidence of the primary studies was assessed using GRADE. RESULTS: Twelve SRs with meta-analyses met the eligibility criteria. The quality of the evidence reported in these SRs varies ranging from low to moderate level. Overall, the available evidence suggests that GbE has potentially beneficial effects over placebo on cognitive performance, activities of daily living, and clinical global impression in the treatment of dementia at doses greater than 200mg/day (usually 240mg/day) administrated for 22 weeks or longer, and that GbE appears to be safe for human consumption. No sufficient evidence supports the favorable effects of GbE administrated for less than 22 weeks. The available evidence consistently indicates that a dose less than 200mg/day of GbE may not be adequate to yield clinical relevant effects in the treatment of dementia. CONCLUSIONS: GbE has potentially beneficial effects for people with dementia when it is administered at doses greater than 200mg/day for at least 5 months. Given the lower quality of the evidence, further rigorously-designed, multicenter-based, large-scale RCTs are warranted.
Asunto(s)
Cognición/efectos de los fármacos , Demencia/tratamiento farmacológico , Ginkgo biloba/química , Nootrópicos/uso terapéutico , Extractos Vegetales/uso terapéutico , Actividades Cotidianas , Demencia/diagnóstico , Demencia/psicología , Relación Dosis-Respuesta a Droga , Humanos , Nootrópicos/efectos adversos , Nootrópicos/aislamiento & purificación , Seguridad del Paciente , Fitoterapia , Extractos Vegetales/efectos adversos , Extractos Vegetales/aislamiento & purificación , Plantas Medicinales , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Resultado del TratamientoRESUMEN
Our group has shown that the polysaccharides extracted from Lycium barbarum (LBP) are neuroprotective for retinal ganglion cells (RGCs) in different animal models. Protecting RGCs from secondary degeneration is a promising direction for therapy in glaucoma management. The complete optic nerve transection (CONT) model can be used to study primary degeneration of RGCs, while the partial optic nerve transection (PONT) model can be used to study secondary degeneration of RGCs because primary degeneration of RGCs and secondary degeneration can be separated in location in the same retina in this model; in other situations, these types of degeneration can be difficult to distinguish. In order to examine which kind of degeneration LBP could delay, both CONT and PONT models were used in this study. Rats were fed with LBP or vehicle daily from 7 days before surgery until sacrifice at different time-points and the surviving numbers of RGCs were evaluated. The expression of several proteins related to inflammation, oxidative stress, and the c-jun N-terminal kinase (JNK) pathways were detected with Western-blot analysis. LBP did not delay primary degeneration of RGCs after either CONT or PONT, but it did delay secondary degeneration of RGCs after PONT. We found that LBP appeared to exert these protective effects by inhibiting oxidative stress and the JNK/c-jun pathway and by transiently increasing production of insulin-like growth factor-1 (IGF-1). This study suggests that LBP can delay secondary degeneration of RGCs and this effect may be linked to inhibition of oxidative stress and the JNK/c-jun pathway in the retina.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lycium/química , Degeneración Nerviosa/etiología , Traumatismos del Nervio Óptico/complicaciones , Traumatismos del Nervio Óptico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Extractos Vegetales/química , Ratas , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Factores de TiempoRESUMEN
Conflicting findings exist regarding the link between environmental factors and development of Alzheimer's disease (AD) in a variety of transgenic mouse models of AD. In the present study, we investigated the effect of behavioral stress on the onset and progression of Aß pathology in the brains of TgCRND8 mice, a transgenic mouse model of AD. One group of TgCRND8 mice was subjected to restraint stress starting at 1 month of age until they were 3 months old, while restraint stress in the second group started at 4 months of age until they were 6 months old. After 2 months of treatment, no differences in the soluble, formic acid extracted, or histologically detected Aß deposition in the cortical and hippocampal levels were found between non-stressed and stressed mice. These results showed that restraint stress alone failed to aggravate amyloid pathology when initiated either before or after the age of amyloid plaque deposition in TgCRND8 mice, suggesting that if stress aggravated AD phenotype, it may not be via an amyloid-related mechanism in the TgCRND8 mice. These findings are indicative that plaque load per se may not be used as a significant criterion for evaluating the effect of stress on AD patients.
Asunto(s)
Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Conducta Animal , Encéfalo/patología , Progresión de la Enfermedad , Placa Amiloide/patología , Estrés Psicológico/patología , Envejecimiento/patología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corticosterona/sangre , Modelos Animales de Enfermedad , Humanos , Hipotálamo/metabolismo , Hipotálamo/patología , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Placa Amiloide/sangre , Placa Amiloide/complicaciones , Proteínas Proto-Oncogénicas c-fos/metabolismo , Restricción Física , Estrés Psicológico/sangre , Estrés Psicológico/complicacionesRESUMEN
The accumulation of ß-amyloid (Aß) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble ß-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Berberina/uso terapéutico , Encéfalo , Trastornos del Conocimiento , Gliosis , Proteínas ADAM/metabolismo , Proteína ADAM10 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Análisis de Varianza , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Cromonas/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/tratamiento farmacológico , Gliosis/etiología , Gliosis/patología , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Morfolinas/farmacología , Mutación/genética , Fragmentos de Péptidos/metabolismo , TransfecciónRESUMEN
One of the major pathological features of Alzheimer's disease (AD) is the appearance of senile plaques characterized by extracellular aggregation of amyloid beta-peptide (Abeta) fibrils. Inhibition of Abeta fibril aggregation is therefore viewed as one possible method to halt the progression of AD. Salvianolic acid B (Sal B) is an active ingredient isolated from Salvia miltiorrhiza, a Chinese herbal medicine commonly used for the treatment of cardiovascular and cerebrovascular disorders. Recent findings show that Sal B prevents Abeta-induced cytotoxicity in a rat neural cell line. To understand the mechanism of Sal B-mediated neuroprotection, its effects on the inhibition of Abeta1-40 fibril formation and destabilization of the preformed Abeta1-40 fibrils were studied. The results were obtained using Thioflavin T fluorescence assay and Abeta aggregating immunoassay. We found that Sal B can inhibit fibril aggregation (IC(50): 1.54-5.37 microM) as well as destabilize preformed Abeta fibril (IC(50): 5.00-5.19 microM) in a dose- and time-dependent manner. Sal B is a better aggregation inhibitor than ferulic acid but less active than curcumin in the inhibition of Abeta1-40 aggregation. In electron microscope study, Sal B-treated Abeta1-40 fibrils are seen in various stages of shortening or wrinkling with numerous deformed aggregates of amorphous structure. Circular dichroism data indicate that Sal B dose dependently prevents the formation of beta-structured aggregates of Abeta1-40. Addition of preincubated Sal B with Abeta1-42 significantly reduces its cytotoxic effects on human neuroblastoma SH-SY5Y cells. These results suggest that Sal B has therapeutic potential in the treatment of AD, and warrant its study in animal models.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/toxicidad , Antioxidantes/farmacología , Benzofuranos/farmacología , Microfibrillas/efectos de los fármacos , Péptidos beta-Amiloides/biosíntesis , Benzotiazoles , Agregación Celular/efectos de los fármacos , Línea Celular Tumoral , Dicroismo Circular , Interpretación Estadística de Datos , Ensayo de Inmunoadsorción Enzimática , Humanos , Microfibrillas/ultraestructura , Microscopía Electrónica , Sales de Tetrazolio , Tiazoles/farmacologíaRESUMEN
This study examined the age-related changes in nitric oxide synthase immunoreactivity (NOS-IR), survival and regeneration of magnocellular neurons in the hypothalamo-neurohypophyseal system (HNS) in rats following hypophysectomy. In adult animal, hypophysectomy induced a significant increase in NOS-IR in the supraoptic (SON), paraventricular nuclei (PVN) and median eminence (ME) by 3 days post-lesion. NOS sustained an increased level until 2 weeks after hypophysectomy and then returned to normal control level. In contrast, at postnatal day 7 (PN7), no obvious increase in NOS-IR was observed in the SON, PVN and ME following the injury compared with age-matched controls. At PN14, the same injury induced an increase in NOS-IR in SON, PVN and ME but the increase was more transient with peak NOS-IR at 3 days and returning to the corresponding control level at 1 week after hypophysectomy. In contrast to a striking age-dependent alteration in NOS-IR in the SON and PVN, hypophysectomy induced substantial degeneration of arginine vasopressin (AVP) and oxytocin (OT) neurons in the SON and PVN in both immature and adult rats and there was no obvious difference in neuronal survival after the same injury among these three groups of different ages by quantitative analysis. Following hypophysectomy, a large number of fibers were observed in the contact zone of the median eminence and the adjacent lumen of the third cerebral ventricle (V3) in adult rats, whereas few fibers could be found in the lumen of the V3 in the immature rats after the same injury. Relationships between NOS induction and magnocellular neuronal survival and regeneration were discussed.