RESUMEN
The deficit in cerebral blood flow (CBF) seen in patients with hypertension-induced vascular dementia is increasingly viewed as a therapeutic target for disease-modifying therapy. Progress is limited, however, due to uncertainty surrounding the mechanisms through which elevated blood pressure reduces CBF. To investigate this, we used the BPH/2 mouse, a polygenic model of hypertension. At 8 mo of age, hypertensive mice exhibited reduced CBF and cognitive impairment, mimicking the human presentation of vascular dementia. Small cerebral resistance arteries that run across the surface of the brain (pial arteries) showed enhanced pressure-induced constriction due to diminished activity of large-conductance Ca2+-activated K+ (BK) channels-key vasodilatory ion channels of cerebral vascular smooth muscle cells. Activation of BK channels by transient intracellular Ca2+ signals from the sarcoplasmic reticulum (SR), termed Ca2+ sparks, leads to hyperpolarization and vasodilation. Combining patch-clamp electrophysiology, high-speed confocal imaging, and proximity ligation assays, we demonstrated that this vasodilatory mechanism is uncoupled in hypertensive mice, an effect attributable to physical separation of the plasma membrane from the SR rather than altered properties of BK channels or Ca2+ sparks, which remained intact. This pathogenic mechanism is responsible for the observed increase in constriction and can now be targeted as a possible avenue for restoring healthy CBF in vascular dementia.
Asunto(s)
Demencia Vascular , Hipertensión , Ratones , Humanos , Animales , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Demencia Vascular/etiología , Demencia Vascular/metabolismo , Músculo Liso Vascular/metabolismo , Arterias Cerebrales/metabolismo , Señalización del Calcio/fisiología , Calcio/metabolismoRESUMEN
African Animal Trypanosomiasis (AAT), caused predominantly by Trypanosoma brucei brucei, T. vivax and T. congolense, is a fatal livestock disease throughout Sub-Saharan Africa. Treatment options are very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1/NT10), in a Leishmania mexicana cell line ('SUPKO') lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3'-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC50s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50>7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable.
Asunto(s)
Trypanosoma congolense , Tripanosomiasis Africana , Animales , Tripanosomiasis Africana/parasitología , Nucleósidos/uso terapéutico , Tubercidina/uso terapéutico , Adenosina/uso terapéutico , Clonación MolecularRESUMEN
The brain microcirculation is increasingly viewed as a potential target for disease-modifying drugs in the treatment of Alzheimer's disease patients, reflecting a growing appreciation of evidence that cerebral blood flow is compromised in such patients. However, the pathogenic mechanisms in brain resistance arteries underlying blood flow defects have not yet been elucidated. Here we probed the roles of principal vasodilatory pathways in cerebral arteries using the APP23 mouse model of Alzheimer's disease, in which amyloid precursor protein is increased approximately sevenfold, leading to neuritic plaques and cerebrovascular accumulation of amyloid-ß similar to those in patients with Alzheimer's disease. Pial arteries from APP23 mice (18 mo old) exhibited enhanced pressure-induced (myogenic) constriction because of a profound reduction in ryanodine receptor-mediated, local calcium-release events ("Ca2+ sparks") in arterial smooth muscle cells and a consequent decrease in the activity of large-conductance Ca2+-activated K+ (BK) channels. The ability of the endothelial cell inward rectifier K+ (Kir2.1) channel to cause dilation was also compromised. Acute application of amyloid-ß 1-40 peptide to cerebral arteries from wild-type mice partially recapitulated the BK dysfunction seen in APP23 mice but had no effect on Kir2.1 function. If mirrored in human Alzheimer's disease, these tandem defects in K+ channel-mediated vasodilation could account for the clinical cerebrovascular presentation seen in patients: reduced blood flow and crippled functional hyperemia. These data direct future research toward approaches that reverse this dual vascular channel dysfunction, with the ultimate aim of restoring healthy cerebral blood flow and improving clinical outcomes.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Señalización del Calcio , Canales de Potasio de Gran Conductancia Activados por el Calcio , Músculo Liso Vascular , Miocitos del Músculo Liso , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/irrigación sanguínea , Arterias Cerebrales/metabolismo , Modelos Animales de Enfermedad , Humanos , Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Ratones , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , VasodilataciónRESUMEN
Rolandic epilepsy is frequent in children but seizures are rarely seen by the physician or captured by video-EEG monitoring. In most children the attacks are few and sporadic and generally occur at night. Also, a high percentage of children with benign epilepsy with centro-temporal spikes (BECTS) have characteristic centro-temporal spikes based on routine EEG monitoring and therefore do not require further tests such as telemetry or sleep studies. We report a video-EEG recording of a seizure in a patient with rolandic epilepsy which may be useful for educational purposes.