RESUMEN
Neuroinflammation is associated with neuronal cell death and could lead to chronic neurodegeneration. This study investigated the neuroprotective potential of virgin coconut oil (VCO) against lipopolysaccharide (LPS)-induced cytotoxicity of neuroblastoma SK-N-SH cells. The findings were validated using Wistar rats, which were fed with 1-10 g/kg VCO for 31 days, exposed to LPS (0.25 mg/kg) and subjected to the Morris Water Maze Test. Brain homogenate was subjected to biochemical analyses and gene expression studies. α-Tocopherol (α-T; 150 mg/kg) served as the positive control. VCO (100 µg/mL) significantly (p < 0.01) improved SK-N-SH viability (+57%) and inhibited reactive oxygen species (-31%) in the presence of LPS. VCO (especially 10 g/kg) also significantly (p < 0.05) enhanced spatial memory of LPS-challenged rats. Brain homogenate of VCO-fed rats was presented with increased acetylcholine (+33%) and reduced acetylcholinesterase (-43%). The upregulated antioxidants may have reduced neuroinflammation [malondialdehyde (-51%), nitric oxide (-49%), Cox-2 (-64%) and iNos (-63%)] through upregulation of IL-10 (+30%) and downregulation of IL-1ß (-65%) and Interferon-γ (-25%). There was also reduced expression of Bace-1 (-77%). VCO-induced neuroprotection, which was comparable to α-T, could be mediated, in part, through inflammatory, cholinergic and amyloidogenic pathways.
Asunto(s)
Lipopolisacáridos , Neuroprotección , Acetilcolinesterasa , Animales , Antiinflamatorios/farmacología , Colinérgicos/farmacología , Aceite de Coco , Lipopolisacáridos/farmacología , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
Chronic cerebral hypoperfusion (CCH) been well characterized as a common pathological status contributing to neurodegenerative diseases such as Alzheimer's disease and vascular dementia. CCH is an important factor that leads to cognitive impairment, but the underlying neurobiological mechanism is poorly understood and no effective treatment is available. Recently, transient receptor potential melastatin 4 (TRPM4) cation channel has been identified as an important molecular element in focal cerebral ischemia. Over activation of the channel is a major molecular mechanism of oncotic cell death. However, the role of TRPM4 in CCH that propagates global brain hypoxia have not been explored. Therefore, the present study is designed to investigate the effect of TRPM4 inhibition on the cognitive functions of the rats following CCH via permanent bilateral occlusion of common carotid arteries (PBOCCA) model. In this model, treatment with siRNA suppressed TRPM4 expression at both the mRNA and protein levels and improved cognitive deficits of the CCH rats without affecting their motor function. Furthermore, treatment with siRNA rescued the LTP impairment in CCH-induced rats. Consistent with the restored of LTP, western blot analysis revealed that siRNA treatment prevented the reduction of synaptic proteins, including calcium/calmodulin-dependent kinase II alpha (CaMKIIα) and brain-derived neurotrophic factor (BDNF) in brain regions of CCH rats. The present findings provide a novel role of TRPM4 in restricting cognitive functions in CCH and suggest inhibiting TRPM4 may represent a promising therapeutic strategy in targeting ion channels to prevent the progression of cognitive deficits induced by ischemia.
Asunto(s)
Isquemia Encefálica/fisiopatología , Hipocampo/fisiopatología , Potenciación a Largo Plazo/fisiología , Memoria Espacial/fisiología , Canales Catiónicos TRPM/fisiología , Animales , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratas Sprague-DawleyRESUMEN
Endophytic fungi have been shown to be a promising source of biologically active natural products. In the present study, extracts of four endophytic fungi isolated from plants of the National Park, Pahang were evaluated for their cytotoxic activity and the nature of their active compounds determined. Those extracts exhibiting activity with IC(50) values less than 17 µg/ml against HCT116, MCF-7 and K562 cell lines were shown to induce apoptosis in these cell lines. Molecular analysis, based on sequences of the rDNA internal transcribed spacers ITS1 and ITS4, revealed all four endophytic fungi to be ascomycetes: three sordariomycetes and a dothideomycete. Six known compounds, cytochalasin J, dechlorogriseofulvin, demethylharzianic-acid, griseofulvin, harzianic acid and 2-hexylidene-3-methyl-succinic acid were identified from a rapid dereplication technique for fungal metabolites using an in-house UV library. The results from the present study suggest the potential of endophytic fungi as cytotoxic agents, and there is an indication that the isolates contain bioactive compounds that mainly kill cancer cells by apoptosis.