RESUMO
More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AßP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AßP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.
Assuntos
Doença de Alzheimer/terapia , Aminoácidos/administração & dosagem , Anticorpos/administração & dosagem , Histamínicos/administração & dosagem , Titânio , Proteínas tau/imunologia , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , HumanosRESUMO
Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Edema Encefálico/prevenção & controle , Cobre/toxicidade , Nanopartículas/toxicidade , Fármacos Neuroprotetores/farmacologia , Ondansetron/farmacologia , Agonistas do Receptor 5-HT3 de Serotonina/farmacologia , Prata/toxicidade , Privação do Sono/fisiopatologia , Animais , Proteínas Sanguíneas/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/fisiopatologia , Química Encefálica/efeitos dos fármacos , Edema Encefálico/etiologia , Edema Encefálico/fisiopatologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/prevenção & controle , Corantes/farmacocinética , Cobre/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Implantes de Medicamento , Azul Evans/farmacocinética , Fadiga/etiologia , Fadiga/fisiopatologia , Fadiga/prevenção & controle , Radioisótopos do Iodo/farmacocinética , Masculino , Nanofios , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Ondansetron/administração & dosagem , Ondansetron/uso terapêutico , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Transtornos de Sensação/etiologia , Transtornos de Sensação/fisiopatologia , Transtornos de Sensação/prevenção & controle , Serotonina/análise , Agonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Agonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Prata/administração & dosagem , Privação do Sono/complicações , Fatores de TempoRESUMO
Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.
Assuntos
Antioxidantes/uso terapêutico , Cobre/toxicidade , Proteínas de Choque Térmico HSP72/biossíntese , Indóis/uso terapêutico , Nanopartículas/toxicidade , Proteínas do Tecido Nervoso/biossíntese , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Prata/toxicidade , Traumatismos da Medula Espinal/tratamento farmacológico , Ubiquitina/biossíntese , Animais , Antioxidantes/farmacologia , Cobre/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Edema/etiologia , Edema/prevenção & controle , Proteínas de Choque Térmico HSP72/genética , Indóis/farmacologia , Masculino , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/farmacologia , Ratos , Ratos Wistar , Dióxido de Silício/administração & dosagem , Dióxido de Silício/toxicidade , Prata/administração & dosagem , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/metabolismo , Vértebras Torácicas , Ubiquitina/genética , Regulação para CimaRESUMO
Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.