RESUMO
Accumulation of metal and the accompanying increase in oxidative stress and inflammation plays an important role in neurodegenerative disease. Deferoxamine (DFO) is a metal chelator found to be beneficial in several animal models of neurodegenerative disease and insult including Alzheimer's disease, Parkinson's disease, stroke, and subarachnoid hemorrhage. In this study, we determine whether intranasally (IN) administered DFO is beneficial in the intracerebroventricular streptozotocin (ICV STZ) rat model of sporadic Alzheimer's disease, which is different from previous models in that it exhibits dysregulation of insulin metabolism as well as oxidative stress and inflammation. Surgical induction of the model included ICV injections of either STZ or citrate buffer (sham in rats), which were treated IN with either saline or DFO (n=10-15/group). Treatment started either before or after injection of STZ to induce the model, and continued throughout the study. IN treatment continued three times per week for three weeks before behavior tests started followed by eventual euthanasia with tissue collection. Spatial memory tests with the Morris water maze showed that STZ rats treated with IN DFO both before and after model induction had significantly shorter escape latencies. Pre-treatment with IN DFO also significantly decreased footslips on the tapered balance beam test. Brain tissue analyses showed DFO treatment decreased oxidation as measured by oxyblot and increased insulin receptor expression. These results further support the potential of IN DFO for use as a treatment for Alzheimer's disease, and show benefit in a non-amyloid/tau rodent model.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Insulinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração Intranasal , Doença de Alzheimer/induzido quimicamente , Animais , Antibióticos Antineoplásicos/toxicidade , Glicemia/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Equilíbrio Postural/efeitos dos fármacos , Ratos , Ratos Long-Evans , Reconhecimento Psicológico/efeitos dos fármacos , Sideróforos/administração & dosagem , Sideróforos/farmacologia , Aprendizagem Espacial/efeitos dos fármacos , Estreptozocina/toxicidadeRESUMO
Deferoxamine (DFO) has shown therapeutic promise for the treatment of Parkinson׳s disease (PD) as it has reduced both behavioral and biochemical deficits when injected into the brain of rodent models of PD. Intranasally administered DFO targets the brain directly but non-invasively and has been effective in animal models of stroke and Alzheimer׳s disease. In this study we sought to determine whether intranasal (IN) DFO could be neuroprotective for PD in a rat model. PD was induced with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, while sham surgery rats received saline injections. Rats were pre-treated three times with either IN DFO or saline (starting 4 days before 6-OHDA), and post-treated twice/wk for one month before behavioral tests. In the apomorphine-induced rotational test, IN DFO significantly decreased the number of contralateral turns after injection of apomorphine HCl (p<0.05). Also, IN DFO significantly decreased limb asymmetry in the rearing tube as measured with contralateral limb touches (p<0.05). The IN DFO treatment yielded a trend towards decreased contralateral foot-slips on the tapered balance beam, though the difference was not significant. Finally, IN DFO-treated rats had increased preservation of tyrosine hydroxylase immunoreactive neurons in the substantia nigra (p<0.05). These results confirm that DFO is beneficial in a 6-OHDA model and demonstrate improvement in motor deficits and dopaminergic neuronal survival with non-invasive intranasal delivery, making this an attractive potential treatment for PD.
Assuntos
Antiparkinsonianos/administração & dosagem , Desferroxamina/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Administração Intranasal , Animais , Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/fisiologia , Lateralidade Funcional , Masculino , Feixe Prosencefálico Mediano/fisiopatologia , Atividade Motora/efeitos dos fármacos , Oxidopamina , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Fotomicrografia , Ratos Long-Evans , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3ß and HIF-1α, with more interleukin-1ß and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3ß and HIF-1α play a prominent role.
Assuntos
Encéfalo/efeitos dos fármacos , Desferroxamina/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Transtornos da Memória/tratamento farmacológico , Proteínas tau/genética , Administração Intranasal/métodos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Glicogênio Sintase Quinase 3 beta , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Sideróforos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder in which motor neurons may be targeted by oxidative and nitrergic stress without sufficient compensation by intrinsic support mechanisms. In this work, we addressed two key tenets of this hypothesis for the pathogenesis of ALS. Using superoxide dismutase (SOD) 1G93A mice, we studied the impact of reduction of nitrergic stress within the CNS with the use of a broad spectrum nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester. A separate cohort of SOD1G93A mice received direct insulin neurotrophic support, ligating receptors expressed upon motor neurons, to attempt protection against neuronal and functional motor dropout. For direct access, we used a novel form of intranasal delivery that provides peak concentration levels in the CNS within 1 h of delivery without systemic side effects at doses which previously rescued retrograde loss of motor axons after axotomy. To identify even minor impacts of these interventions on the outcome, we utilized an intensive program of serial behavioral and electrophysiological testing weekly, combined with endpoint quantitative morphometry and molecular analysis. This intensive evaluation enhanced our knowledge of the time course in SOD1G93A mice and impact of the SOD1G93A mutation upon motor neurons and their function. Neither intervention had even minimal impact upon slowing progression of disease in SOD1G93A mice. Our data argue against significant roles for nitrergic stress in promoting motor neuron loss and the importance of alternative neurotrophic support mechanisms that might support motor neurons and prevent disease progression in SOD1G93A mice.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Insulina/administração & dosagem , NG-Nitroarginina Metil Éster/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Administração Intranasal , Fatores Etários , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Mutação/genética , Condução Nervosa/efeitos dos fármacos , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/patologia , Nervos Periféricos/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Medula Espinal/patologia , Superóxido Dismutase/genéticaRESUMO
We determined the nervous system targeting of interferon-beta1b (IFN-beta1b), a 20 kDa protein used to treat the relapsing-remitting form of multiple sclerosis, following intranasal administration in anesthetized, adult cynomolgus monkeys. Five animals received an intranasal bolus of [(125)I]-labeled IFN-beta1b, applied bilaterally to the upper nasal passages. Serial blood samples were collected for 45 min, after which the animals were euthanized by transcardial perfusion-fixation. High resolution phosphor imaging of tissue sections and gamma counting of microdissected tissue were used to obtain the distribution and concentration profiles of [(125)I]-IFN-beta1b in central and peripheral tissues. Intranasal administration resulted in rapid, widespread targeting of nervous tissue. The olfactory bulbs and trigeminal nerve exhibited [(125)I]-IFN-beta1b levels significantly greater than in peripheral organs and at least one order of magnitude higher than any other nervous tissue area sampled. The basal ganglia exhibited highest [(125)I]-IFN-beta1b levels among CNS regions other than the olfactory bulbs. Preferential IFN-beta1b distribution to the primate basal ganglia is a new finding of possible clinical importance. Our study suggests both IFN-beta and IFN-alpha, which share the same receptor, may be bound with relatively high affinity in these structures, possibly offering new insight into a neurovegetative syndrome induced by IFN-alpha therapy and suspected to involve altered dopamine neurotransmission in the basal ganglia. Most importantly, our results suggest intranasally applied macromolecules may bypass the blood-brain barrier and rapidly enter the primate CNS along olfactory- and trigeminal-associated extracellular pathways, as shown previously in the rat. This is the first study to finely detail the central distribution of a labeled protein after intranasal administration in non-human primates.
Assuntos
Interferon beta/farmacocinética , Sistema Nervoso/efeitos dos fármacos , Mucosa Olfatória/efeitos dos fármacos , Administração Intranasal , Animais , Autorradiografia , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Mapeamento Encefálico , Líquido Extracelular/efeitos dos fármacos , Líquido Extracelular/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/metabolismo , Fatores Imunológicos/farmacocinética , Interferon beta/administração & dosagem , Interferon beta/metabolismo , Radioisótopos do Iodo , Macaca , Masculino , Sistema Nervoso/imunologia , Sistema Nervoso/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Bulbo Olfatório/metabolismo , Mucosa Olfatória/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Radioimunoensaio , Receptores de Interferon/efeitos dos fármacos , Receptores de Interferon/metabolismo , Nervo Trigêmeo/efeitos dos fármacos , Nervo Trigêmeo/metabolismoRESUMO
Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimer's disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Cognição/efeitos dos fármacos , Insulina/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , Idoso , Doença de Alzheimer/epidemiologia , Comorbidade , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Masculino , Transtornos da Memória/epidemiologia , Medição de Risco/métodos , Fatores de Risco , Resultado do Tratamento , Washington/epidemiologiaRESUMO
We investigated the CNS delivery of insulin-like growth factor-I (IGF-I), a 7.65 kDa protein neurotrophic factor, following intranasal administration and the possible pathways and mechanisms underlying transport from the nasal passages to the CNS. Anesthetized adult male Sprague-Dawley rats were given [125I]-IGF-I intranasally or intravenously and then killed by perfusion-fixation within 30 min. Other animals were killed following cisternal puncture and withdrawal of cerebrospinal fluid (CSF) or intranasal administration of unlabeled IGF-I or vehicle. Both gamma counting of microdissected tissue and high resolution phosphor imaging of tissue sections showed that the tissue concentrations and distribution following intranasal administration were consistent with two routes of rapid entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages with the olfactory bulbs and rostral brain regions (e.g. anterior olfactory nucleus and frontal cortex) and the other associated with the peripheral trigeminal system connecting the nasal passages with brainstem and spinal cord regions. Intranasal administration of [125I]-IGF-I also targeted the deep cervical lymph nodes, consistent with their possible role in lymphatic drainage of both the nasal passages and the CNS. Cisternal CSF did not contain [125I]-IGF-I following intranasal administration. Intravenous [125I]-IGF-I resulted in blood and peripheral tissue exposure similar to that seen following intranasal administration but CNS concentrations were significantly lower. Finally, delivery of IGF-I into the CNS activated IGF-I signaling pathways, confirming some portion of the IGF-I that reached CNS target sites was functionally intact. The results suggest intranasally delivered IGF-I can bypass the blood-brain barrier via olfactory- and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.
Assuntos
Encéfalo/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/administração & dosagem , Nervo Olfatório/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Nervo Trigêmeo/efeitos dos fármacos , Administração Intranasal , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Relação Dose-Resposta a Droga , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacocinética , Radioisótopos do Iodo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Masculino , Nervo Olfatório/citologia , Nervo Olfatório/metabolismo , Condutos Olfatórios/citologia , Condutos Olfatórios/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Nervo Trigêmeo/citologia , Nervo Trigêmeo/metabolismoRESUMO
Intranasal (i.n.) administration of IFN beta-1b was examined as a route for targeted delivery to the rat central nervous system (CNS). Intranasal administration resulted in significant delivery throughout the CNS and cervical lymph nodes with low delivery to peripheral organs. At similar blood levels, intravenous (i.v.) administration of IFN beta-1b yielded 88-98% lower CNS levels and 100-1650% greater peripheral organ levels compared to intranasal. Autoradiography confirmed much greater delivery to the CNS with intranasal administration. Intranasally administered IFN beta-1b reached the brain intact and produced tyrosine phosphorylation of IFN receptor in the CNS. Intranasal administration offers a non-invasive method of drug delivery for multiple sclerosis (MS) that bypasses the blood-brain barrier (BBB) and directly targets the CNS and lymph nodes.
Assuntos
Barreira Hematoencefálica/fisiologia , Sistema Nervoso Central/química , Imunossupressores/administração & dosagem , Interferon beta/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Administração Intranasal , Animais , Autorradiografia , Western Blotting , Química Encefálica , Sistema Nervoso Central/metabolismo , Vértebras Cervicais , Imunossupressores/metabolismo , Injeções Intravenosas , Interferon beta/metabolismo , Linfonodos , Masculino , Ratos , Distribuição TecidualRESUMO
Neurotrophic factors are proteins with considerable potential in the treatment of central nervous system (CNS) diseases and traumatic injuries. However, a significant challenge to their clinical use is the difficulty associated with delivering these proteins to the CNS. Neurotrophic factors are hydrophilic, typically basic, monomeric or dimeric proteins, mostly in the size range of 5 to 30 kDa. Neurotrophic factors potently support the development, growth and survival of neurons, eliciting biological effects at concentrations in the nanomolar to femtomolar range. They are not orally bioavailable and the blood-brain and blood-cerebrospinal fluid barriers severely limit their ability to enter into and act on sites in the CNS following parenteral systemic routes of administration. Most neurotrophic factors have short in vivo half-lives and poor pharmacokinetic profiles. Their access to the CNS is restricted by rapid enzymatic inactivation, multiple clearance processes, potential immunogenicity and sequestration by binding proteins and other components of the blood and peripheral tissues. The development of targeted drug delivery strategies for neurotrophic factors will probably determine their clinical effectiveness for CNS conditions. Achieving significant CNS target site concentrations while limiting systemic exposure and distribution to peripheral sites of action will lessen unwanted pleiotropic effects and toxicity. Local introduction of neurotrophic factors into the CNS intraparenchymally by direct injection/infusion or by implantation of delivery vectors such as polymer matrices or genetically modified cells yields the highest degree of targeting, but is limited by diffusion restrictions and invasiveness. Delivery of neurotrophic factors into the cerebrospinal fluid (CSF) following intracerebroventricular or intrathecal administration is less invasive and allows access to a much wider area of the CNS through CSF circulation pathways. However, diffusional and cellular barriers to penetration into surrounding CNS tissue and significant clearance of CSF into the venous and lymphatic circulation are also limiting. Unconventional delivery strategies such as intranasal administration may offer some degree of CNS targeting with minimal invasiveness. This review presents a summary of the neurotrophic factors and their indications for CNS disorders, their physicochemical characteristics and the different approaches that have been attempted or suggested for their delivery to the CNS. Future directions for further research such as the potential for CNS disease treatment utilising combinations of neurotrophic factors, displacement strategies, small molecule mimetics, chimaeric molecules and gene therapy are also discussed.
Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Fatores de Crescimento Neural , Animais , Combinação de Medicamentos , Humanos , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/farmacocinética , Fatores de Crescimento Neural/fisiologiaRESUMO
BACKGROUND: Insulin-like growth factor-I (IGF-I) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this invasive method of administration is not practical for the large number of individuals who require treatment for stroke. Intranasal (IN) delivery offers a noninvasive method of bypassing the blood-brain barrier (BBB) to deliver IGF-I and other neurotrophic factors to the brain. Here, we demonstrate for the first time the therapeutic benefit of IN IGF-1 in rats following middle cerebral artery occlusion (MCAO). METHODS: A blinded, vehicle-controlled study of IN IGF-I was performed using the intraluminal suture occlusion model. Rats were randomly divided into vehicle-control, 37.5 and 150 microg IGF-I-treated groups. Treatments occurred at 10 min after onset of 2 h of MCAO, and then 24 and 48 h later. Four neurologic behavioral tests were performed 4, 24, 48 and 72 h after the onset of MCAO. Corrected infarct volumes were evaluated 72 h after the onset of MCAO. RESULTS: Treatment with the 150 microg IGF-I significantly reduced the infarct volume by 63% vs. control (p=0.004), and improved all the neurologic deficit tests of motor, sensory, reflex and vestibulomotor functions (p<0.01). However, the 37.5 microg dose of IGF-I was ineffective. CONCLUSION: While IGF-I does not cross the BBB efficiently, it can be delivered to the brain directly from the nasal cavity following IN administration, bypassing the BBB. IN IGF-I markedly reduced infarct volume and improved neurologic function following focal cerebral ischemia. This noninvasive, simple and cost-effective method is a potential treatment for stroke.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fator de Crescimento Insulin-Like I/farmacologia , Fármacos Neuroprotetores/farmacologia , Administração Intranasal , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Barreira Hematoencefálica/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/fisiopatologia , Exame Neurológico , Paresia/tratamento farmacológico , Paresia/etiologia , Paresia/fisiopatologia , Postura/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Transtornos de Sensação/tratamento farmacológico , Transtornos de Sensação/etiologia , Transtornos de Sensação/fisiopatologiaRESUMO
Insulin-like growth factor-I (IGF-I) has been proposed as a treatment for stroke. However, it does not efficiently cross the blood-brain barrier (BBB). Intracerebroventricular injection of IGF-I has been shown to offer protection against cerebral ischemic damage in rats although this invasive method of administration may not be practical in humans. Non-invasive intranasal (IN) delivery of IGF-I to the brain is a promising alternative. We have assessed the therapeutic effect of IN IGF-I in rats following middle cerebral artery occlusion (MCAO). Treatment was initiated 10 min after the onset of MCAO and then again 24 and 48 h later. Intranasal dosing of 75 microg IGF-1 (225 microg total IGF-I over 48 h) significantly reduced corrected infarct volumes by 60% vs. control (P<0.01) and hemispheric swelling by 45.6% vs. control (P<0.05). Neurologic function, assessed by the postural reflex, flexor response and adhesive tape tests, was also improved by IN IGF-I as compared to control. Our study indicates IN delivery of IGF-1 holds significant promise as a non-invasive and efficacious method of bypassing the BBB for the treatment of stroke.
Assuntos
Administração Intranasal , Isquemia Encefálica/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fator de Crescimento Insulin-Like I/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Edema Encefálico/prevenção & controle , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Esquema de Medicação , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Mucosa Olfatória/citologia , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologiaRESUMO
In a retrospective cliniconeuropathological study, we reviewed all the cases received in our dementia brain bank during a 4-year period to determine if all patients with severe substantia nigra (SN) degeneration and SN Lewy bodies (LBs) exhibited prominent signs of parkinsonism and were treated for parkinsonism during the disease course. The SN of 426 cases were graded for microscopic degeneration using a semiquantitative five-tiered scale, with grade 0 indicating normal and grade 4 the most severe degeneration. Twenty-nine cases with grade 3 (16) or grade 4 (13) SN degeneration with SN LBs and clinical records were identified. Ten had been treated for parkinsonism (6 grade 3, 4 grade 4) and 19 had not. Whereas most of the patients had exhibited signs of end-stage parkinsonism during their last year, 1 grade 3 and 2 grade 4 patients apparently never exhibited prominent signs of parkinsonism during the course of their dementia. No clear neuropathological differences were noted between these patients that did not have prominent signs and a control group of six patients with clinical Parkinson's disease with dementia (parkinsonism onset at least 1 year before dementia onset). We conclude that in patients with dementia there is an inconsistent relationship between the expression of clinical parkinsonism during life and severe SN degeneration with LBs identified at necropsy.
Assuntos
Demência/patologia , Degeneração Neural/patologia , Doença de Parkinson/patologia , Substância Negra/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVES: To identify patients with pure hippocampal sclerosis (HS) as a cause of dementia, to determine whether they have had histories of hypotension or hypoxia, and to compare the clinical features of patients with pure HS with a control group of AD patients without HS. METHODS: In a retrospective study, the authors reviewed all 1771 cases received in their dementia brain bank from 1978 through 1996 to identify those patients with pure HS, defined as severe degeneration and gliosis of the CA1 sector and subiculum of the hippocampal formation in the absence of other significant dementing disease such as Alzheimer's changes. The control group included all patients received during the same period with severe AD without HS, infarcts, or other dementing disease. RESULTS: Seven pure HS cases (0.4%) were identified. None had any episodes of syncope, hypotension, or hypoxia reported in association with dementia onset. Six had memory loss as the primary presenting symptom, and all became progressively demented. Forty-five AD patients without HS were identified for the control group. There were no clear clinical differences between the two groups with regard to sex, age at onset, risk factors for vascular disease, symptoms of cerebrovascular disease, treatment with tranquilizing medications, treatment for depression, or nursing home placement. There was a tendency for heart disease to be more prevalent and the duration of illness to be shorter in the patients with pure HS. CONCLUSIONS: Pure hippocampal sclerosis (HS) occurred in only 0.4% of our dementia patients. Clinically, the seven patients with pure HS were similar to our AD control group. Further research is needed to determine the causes of HS and why HS appears to mimic AD.
Assuntos
Doença de Alzheimer/patologia , Demência/patologia , Hipocampo/patologia , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Masculino , EscleroseRESUMO
The 1996 research report by Hoener et al. [M.C. Hoener, E. Hewitt, J. M. Conner, J.W. Costello, S. Varon, Nerve growth factor (NGF) content in adult rat brain tissue is several-fold higher than generally reported and is largely associated with sedimentable fractions, Brain Res. 728 (1996) 47-56.] compares levels of nerve growth factor (NGF) found in rat brain by assaying both supernatant and pellet to previously reported data. However, Hoener et al. miscalculated when converting values previously reported in the literature to units of picogram per milliliter. Regardless of this mistake, the method of tissue extraction does affect the extent of release of NGF, which must be maximized in order to accurately determine NGF levels in the central nervous system. We now report that accurate measurement of NGF levels is not only affected by the incomplete release of NGF from receptors, but also the medium in which the standard curve is run. It is the combination of these two variables that has led to the underestimation of NGF levels in previous research.
Assuntos
Fatores de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Animais , Anticorpos Monoclonais/análise , Química Encefálica , Meios de Cultura , Ensaio de Imunoadsorção Enzimática , Masculino , Fatores de Crescimento Neural/análise , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/análiseRESUMO
In a retrospective clinicopathological study, we examined the substantia nigra (SN) of 48 dementia patients with SN Lewy bodies (LBs) to determine if the severity of degeneration correlated with either the occurrence of signs of parkinsonism at dementia presentation or with the frequency of treatment for parkinsonism during the disease course. The SN specimens were graded for microscopic degeneration using a semi-quantitative five-tiered scale. Whereas no correlation was found between the grade of degeneration and occurrence of signs at presentation (r = -0.16, p = 0.18), with 16 of 38 patients having had signs reported, a more severe grade was statistically correlated with an increased frequency of treatment during the course (r = 0.41, p = 0.004), with ten of 41 patients having been treated for parkinsonism. Contrary to our expectations, we found that fewer than half of the patients with the two most severe grades of degeneration presented with signs of parkinsonism or were ever treated for parkinsonism.
Assuntos
Demência/complicações , Demência/patologia , Corpos de Lewy/patologia , Doença de Parkinson/complicações , Substância Negra/patologia , Idoso , Antipsicóticos/uso terapêutico , Humanos , Degeneração Neural/patologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Estudos RetrospectivosRESUMO
Loss of memory and cholinergic transmission are associated with both Alzheimer's disease (AD) and marijuana use. The human brain muscarinic acetylcholine receptor (mAChR), which is involved in memory function and is inhibited by arachidonic acid, is also inhibited by anandamides. Two agonists of the cannabinoid receptor derived from arachidonic acid, anandamide (AEA) and R-methanandamide, inhibit ligand binding to the mAChR. Binding of the mAChR antagonist [3H]quinuclidinyl benzilate ([3H]QNB) is inhibited up to 89% by AEA (half-maximal inhibition at 50 microM). Binding of the more polar antagonist [N-methyl-3H]scopolamine ([3H]NMS) is inhibited by AEA up to 76% (half-maximal inhibition at 44 microM). R-methanandamide inhibits more than 90% of both [3H]QNB binding (I50 = 34 microM) and [3H]NMS binding (I50 = 15 microM) to the mAChR. Both AEA and R-methanandamide stimulate mAChR binding of the agonist [3H]oxotremorine-M at low concentrations (25-75 microM), but significantly inhibit agonist binding at higher concentrations (I50 = 150 microM). The cannabinoid antagonist SR141716A did not alter AEA or R-methanandamide inhibition of [3H]NMS binding to the mAChR, even at concentrations as high as 1 microM. Further, the cannabinoid agonist WIN 55212-2 does not alter antagonist binding to the mAChR. This demonstrates that mAChR inhibition by the anandamides is not mediated by the cannabinoid receptor. Since AEA and R-methanandamide are structurally similar to arachidonic acid, they may interact with the mAChR in a similar manner to inhibit receptor function.
Assuntos
Ácidos Araquidônicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismo , Ácido Araquidônico/metabolismo , Ligação Competitiva , Endocanabinoides , Humanos , Alcamidas Poli-Insaturadas , Receptores de Canabinoides , Receptores de Droga/efeitos dos fármacos , Receptores de Droga/metabolismoRESUMO
Arachidonic acid (AA) inhibits the binding of [3H]quinclidinyl benzilate ([3H]QNB) to the human brain muscarinic cholinergic receptor (mAChR). AA inhibits at lower concentrations in the absence of glutathione (I50 = 15 microM) than in the presence of glutathione (I50 = 42 microM). Inhibition of mAChR binding shows specificity for AA and is reduced with loss of one or more double bonds or with either a decrease or increase in the length of the fatty acid chain. Metabolism of AA by the lipoxygenase, epoxygenase, or fatty acid cyclooxygenase pathways is not required for the inhibitory activity of AA on mAChR binding. Inhibition of [3H]QNB binding by AA is reversible. While decreasing Bmax, AA increased the apparent KD for [3H]QNB and for the more polar antagonist [3H]NMS. In addition, AA inhibits binding of the agonist [3H]oxotremorine-M (I50 = 60 microM) and is the first mediator of mAChR action to be shown to reversibly inhibit mAChR binding. The feedback inhibition of the mAChR by AA may serve a homeostatic function similar to the reuptake and hydrolysis of acetylcholine following cholinergic nerve transmission.
Assuntos
Ácidos Araquidônicos/farmacologia , Agonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/metabolismo , Quinuclidinil Benzilato/metabolismo , Receptores Muscarínicos/metabolismo , Adulto , Ácidos Araquidônicos/metabolismo , Cromanos/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Retroalimentação , Lobo Frontal/metabolismo , Glutationa/farmacologia , Humanos , Cinética , Manganês/farmacologia , N-Metilescopolamina/metabolismo , Oxotremorina/análogos & derivados , Oxotremorina/metabolismo , Ácido Palmítico/farmacologiaRESUMO
Free D-Ser, D-Asp and total D-amino acids were significantly higher (p < 0.05) in Alzheimer (AD) ventricular CSF than in normal CSF. There was no significant difference in the total L-amino acids between AD and normal CSF, but L-Gln and L-His were significantly higher (p < 0.05) in AD-CSF. The higher concentrations of these D- and L-amino acids in AD ventricular CSF could reflect the degenerative process that occurs in Alzheimer's brain since ventricular CSF is the repository of amino acids from the brain.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Aminoácidos/líquido cefalorraquidiano , HumanosRESUMO
"This article makes the case that the new immigration [to the U.S. from developing Latin American and Asian countries], motivated by kinship ties and family reunification provisions of U.S. immigration law, leads to a clustering of new immigrants into areas that are no longer attracting large numbers of native-born Americans. It is argued that the concentration of these groups into ¿high immigration regions' will limit their access to employment and education opportunities that would facilitate their spatial assimilation and upward mobility."
Assuntos
Aculturação , Etnicidade , Família , Geografia , Preconceito , Política Pública , Mobilidade Social , Fatores Socioeconômicos , América , Cultura , Demografia , Países Desenvolvidos , Economia , Características da Família , América do Norte , População , Características da População , Classe Social , Estados UnidosRESUMO
"This paper assesses the impacts of low-skilled immigration on the interstate migration of...U.S.-born low-skilled Americans, based on the disaggregated data of the 1990 Census. Our results reveal that the push effects of...immigration on the departure process [were] much stronger than its discouraging and complementary effects on the destination choice process; and that the push effects of low-skilled immigration are (1) stronger on whites than on non-whites, (2) much stronger on the poor than on the non-poor, (3) weaker on the 15-24 age group than on older age groups, and (4) the strongest on poor whites."