RESUMO
Numerous studies relate the onset and severity of multiple sclerosis (MS) with viral infections. Herpes simplex virus type 1 (HSV-1), which is neurotropic and highly prevalent in the brain of healthy individuals, has been proposed to relate to MS. Here, we review and discuss the reported connections between HSV-1 and MS.
Assuntos
Infecções por Vírus Epstein-Barr , Herpes Simples , Herpesvirus Humano 1 , Esclerose Múltipla , Viroses , Humanos , DNA ViralRESUMO
Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. Aquaporin 4 (AQP4) water channels on astrocytic end feet regulate the solute transport of the glymphatic system, facilitating the exchange of compounds between the brain parenchyma and the cerebrospinal fluid (CSF), which is important for the clearance of waste away from the brain. Wistar rats, subjected to either pneumococcal meningitis or artificial CSF (sham control), received Evans blue-albumin (EBA) intracisternally. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the CSF compartments compared to the uninfected sham group. Our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the blood-brain barrier (BBB) vascular endothelium, which leads to misplacement of AQP4 with the consequent loss of the AQP4 water channel's functionality. IMPORTANCE The lack of solute drainage due to a dysfunctional glymphatic system leads to an increase of the neurotoxic bacterial material in the CSF compartments of the brain, ultimately leading to brain-wide neuroinflammation and neuronal damage with consequent impairment of neurological functions. The loss of function of the glymphatic system can therefore be a leading cause of the neurological sequelae developing post-bacterial meningitis.
Assuntos
Sistema Glinfático , Meningite Pneumocócica , Animais , Ratos , Albuminas/metabolismo , Aquaporina 4/genética , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Sistema Glinfático/metabolismo , Meningite Pneumocócica/metabolismo , Ratos WistarRESUMO
Tumorigenic cell lines are more susceptible to [Re6Se8I6]3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.
Assuntos
Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Complexos de Coordenação/farmacologia , Rênio/farmacologia , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Humanos , Selênio/farmacologia , Distribuição Tecidual/efeitos dos fármacosRESUMO
Neurodegenerative disorders (NDDs) are characterized by the progressive loss of structure or neuron function, often associated with neuronal death. Treatments for neurodegenerative diseases only address symptoms without having any disease-modifying effect but serious side effects. Currently, there is no effective treatment for NDDs. This is due to the poor flow of drugs to the blood-barrier brain (BBB) which does not allow macromolecules like proteins and peptides to pass through it. Targeted drug delivery to the central nervous system (CNS) for the diagnosis and treatment of NDDs, such as Alzheimer's disease (AD), is restricted due to the limitations posed by the BBB as well as opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Nanotechnology thereby presents a broad approach for transporting molecules through the BBB, thus allowing the entry of substances acting directly on the site affected by the disease. The aim of this review is to outline current strategies in nanotechnology for treating Alzheimer's and Parkinson's diseases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Nanotecnologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Barreira Hematoencefálica/química , Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/metabolismoRESUMO
Moderate traumatic brain injury (TBI) might increase the vulnerability to neuronal neurodegeneration, but the basis of such selective neuronal susceptibility has remained elusive. In keeping with the disruption of the blood-brain barrier (BBB) caused by TBI, changes in BBB permeability following brain injury could facilitate the access of xenobiotics into the brain. To test this hypothesis, here we evaluated whether TBI would increase the susceptibility of nigrostriatal dopaminergic fibers to the systemic administration of 6-hydroxydopamine (6-OHDA), a classic neurotoxin used to trigger a PD-like phenotype in mice, but that in normal conditions is unable to cross the BBB. Adult Swiss mice were submitted to a moderate TBI using a free weight-drop device and, 5h later, they were injected intraperitoneally with a single dose of 6-OHDA (100mg/kg). Afterwards, during a period of 4weeks, the mice were submitted to a battery of behavioral tests, including the neurological severity score (NSS), the open field and the rotarod. Animals from the TBI plus 6-OHDA group displayed significant motor and neurological impairments that were improved by acute l-DOPA administration (25mg/kg, i.p.). Moreover, the observation of the motor deficits correlates with (i) a significant decrease in the tyrosine hydroxylase levels mainly in the rostral striatum and (ii) a significant increase in the levels of striatal glial fibrillary acidic protein (GFAP) levels. On the whole, the present findings demonstrate that a previous moderate TBI event increases the susceptibility to motor, neurological and neurochemical alterations induced by systemic administration of the dopaminergic neurotoxin 6-OHDA in mice.