RESUMEN
Treatments for neurologic diseases are often limited in efficacy due to poor spatial and temporal control over their delivery. Intracerebral delivery partially overcomes this by directly infusing therapeutics to the brain. Brain structures, however, are nonuniform and irregularly shaped, precluding complete target coverage by a single bolus without significant off-target effects and possible toxicity. Nearly complete coverage is crucial for effective modulation of these structures. We present a framework with computational mapping algorithms for neural drug delivery (COMMAND) to guide multi-bolus targeting of brain structures that maximizes coverage and minimizes off-target leakage. Custom-fabricated chronic neural implants leverage rational fluidic design to achieve multi-bolus delivery in rodents through a single infusion of radioactive tracer (Cu-64). The resulting spatial distributions replicate computed spatial coverage with 5% error in vivo, as detected by positron emission tomography. COMMAND potentially enables accurate, efficacious targeting of discrete brain regions.
Asunto(s)
Biología Computacional/métodos , Sistemas de Liberación de Medicamentos/métodos , Implantes de Medicamentos/metabolismo , Preparaciones Farmacéuticas/metabolismo , Algoritmos , Animales , Humanos , RatonesRESUMEN
The ATP-binding cassette transporter A1 (ABCA1) is a membrane bound protein that serves to efflux cholesterol and phospholipids onto lipid poor apolipoproteins during HDL biogenesis. Increasing the expression and activity of ABCA1 have beneficial effects in experimental models of various neurologic and cardiovascular diseases including Alzheimer's disease. Despite the beneficial effects of liver X receptor (LXR) agonists--compounds that increase ABCA1 expression--in preclinical studies, their therapeutic utility is limited by systemic adverse effects on lipid metabolism. Interestingly, microRNA-33 (miR-33) inhibition increases ABCA1 expression and activity in rodents and non-human primates without severe metabolic adverse effects. Herein, we demonstrate that treatment of cultured mouse neurons, astrocytes and microglia with an antisense oligonucleotide (ASO) targeting miR-33 increased ABCA1 expression, which was accompanied by increased cholesterol efflux and apoE secretion in astrocytic cultures. We also show that intracerebral delivery of an ASO targeting miR-33 leads to increased ABCA1 expression in cerebral cortex or subcortical structures such as hippocampus. These findings highlight an effective strategy for increasing brain ABCA1 expression/activity for relevant mechanistic studies. [Corrected]
Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , Encéfalo/efectos de los fármacos , MicroARNs/antagonistas & inhibidores , Oligonucleótidos Antisentido/farmacología , Animales , Apolipoproteínas E/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/metabolismo , Línea Celular , Colesterol/metabolismo , Inyecciones Intraventriculares , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Cultivo Primario de CélulasRESUMEN
Studies in rats, involving hippocampal lesions and hippocampal drug infusions, have implicated the hippocampus in the modulation of anxiety-related behaviors and conditioned fear. The ventral hippocampus is considered to be more important for anxiety- and fear-related behaviors than the dorsal hippocampus. In the present study, we compared the role of dorsal and ventral hippocampus in innate anxiety and classical fear conditioning in Wistar rats, examining the effects of temporary pharmacological inhibition by the GABA-A agonist muscimol (0.5 ug/0.5 ul/side) in the elevated plus maze and on fear conditioning to a tone and the conditioning context. In the elevated plus maze, dorsal and ventral hippocampal muscimol caused distinct behavioral changes. The effects of ventral hippocampal muscimol were consistent with suppression of locomotion, possibly accompanied by anxiolytic effects, whereas the pattern of changes caused by dorsal hippocampal muscimol was consistent with anxiogenic effects. In contrast, dorsal and ventral hippocampal muscimol caused similar effects in the fear conditioning experiments, disrupting contextual, but not tone, fear conditioning.
Asunto(s)
Ansiedad/fisiopatología , Condicionamiento Psicológico/fisiología , Miedo/fisiología , Hipocampo/fisiología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Masculino , Muscimol/farmacología , Ratas , Ratas WistarRESUMEN
Place memory is relevant for exploration and forage behaviour. When food supply is dispersed, a win-shift has advantage over a win-stay strategy. In the Olton Octagonal Maze, the rat follows a win-shift strategy using working memory. However, in the Olton 4x4 version, the rat follows a win-stay strategy, using both working and long-term memories. It has been suggested that the neocortex is required for the resolution of tasks demanding long-term, but not for that demanding working memory alone. The role of anteromedial/posterior parietal cortex (AM/PPC) was investigated here, using a reversible lesion induced by intracerebral lidocaine infusion. Long-Evans rats were implanted with guide cannulae into the AM/PPC and trained in an Olton 4x4 maze, counting working and long-term memory errors after a delay. Then, the animals were infused with lidocaine or saline during the delay phase and tested for three days. Another series of animals, treated as before, was tested in an Olton Octagonal Maze and subjected to the same injection schedule. In the Olton 4x4 Maze, lidocaine produced a significant increase in working and long-term memory errors, compared to saline and post-lidocaine conditions. In contrast, in the Olton Octagonal Maze, lidocaine did not induce any effect on working memory errors. Thus, AM/PPC is required when both working with previous information and long-term memories are needed, but not when only working memory is required, as it happens under ethological conditions. Whenever food supply is dispersed, a win-shift strategy is preferable.