RESUMO
Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and Oatp14 proteins localize to both the luminal and abluminal microvessel membranes. In human and rodent choroid plexus epithelial cells, MCT8 is concentrated on the epithelial cell apical surface and OATP14 localizes primarily to the basal-lateral surface. Mct8 and Oatp14 expression was also observed in mouse and rat tanycytes, which are thought to form a barrier between hypothalamic blood vessels and brain. These results raise the possibility that reduced thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations. The high microvessel expression of OATP14 in rodent compared with human brain may contribute to the relatively mild phenotype observed in Mct8-null mice, in contrast to humans lacking functional MCT8.
Assuntos
Barreira Hematoencefálica/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Western Blotting , Linhagem Celular , Células Cultivadas , Cérebro/irrigação sanguínea , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Microvasos/citologia , Microvasos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SimportadoresRESUMO
Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.
