Neurodegeneration Group
Neurodegenerative diseases and their treatment
Our laboratory is interested in the study of neurodegenerative diseases, with special emphasis on the search of new therapeutic strategies, assessing the biochemical pharmacological mechanism of action of different drugs. Our approach is multidisciplinary, given that we use pharmacological, biochemical, cellular biological or histological techniques, in assays with post-mortem samples from patients, experimental models in vivo or cells in culture.
Research lines:
1. In the past we have been interested in the study of Parkinson’s disease (PD) pathophysiology, in particular the contribution of the peptidergic alterations. At present we have studied new synthetic molecules with antiparkinsonain potential, and the relationship between cerebral levodopa (LD) influx and short-term antiparkinsonian and dyskinetic responses to LD in PD patients. In addition we have investigated the consequences of LD therapy in MPTP treated mice and the appearance of tyrosine hydroxylase striatal neurons and the impact of the deletion of Nrf2, a transcription factor guardian of redox homeostasis, on dopamine (DA) neuron death and inflammation (glial activation).
2. Concerning our research activity on Alzheimer’s disease (AD) we have studied β-amyloid (Aβ) toxicity both in vitro and in vivo, as experimental models. We have investigated the brain oxidative status of AD in comparison with that of Aβ repeatedly intraventricularly injected rats. We have demonstrated that Aβ modulation of glutamate uptake in neurons or astrocytes in culture is a survival mechanism.
3. Modulation of glial activation as a therapeuctic target for neurodegenerative diseases. We are investigating the potential of cannabinoids to decrease microglial activation both in vitro and in vivo, and the relevance of this mechanism in the context of AD. Indeed, cannabinoids are neuroprotective and anti-inflammatory agents.
4. We have begun to use neuroimaging in vivo to follow the progression of disease and the effects of treatments. This strategy include, proton magnetic resonance, in vivo spectroscopy and positron emission tomography (PET) studies used in longitudinal studies in APP transgenic mice, as model of the neurologic condition.
Scientific contributions:
. Glycosidic DA derivatives behave as DA prodrugs: they have demonstrated to be stable in plasma, to release DA when incubated with brain extracts and to interact with the glucose transporter-1 in a structure relationship.
. We have demonstrated marked alterations in cannabinoid receptor localization, expression and function in AD brain. Furthermore cannabinoids prevent Aβ-induced microglial activation and neurodegeneration both in vitro and in vivo. Prolonged oral or subchronic systemic treatment with cannabinoid agonists, including those without psychoactive effects (JWH-133 and cannabidiol) counteract cognitive deficits, decreased motor activity and inflammatory mediators (TNF-α, IL-6, COX-2) in APP transgenic mice.
. Cannabinoids decrease NO generation, promote microglial migration and decrease ATP-induced intracellular calcium by both cannabinoid receptor dependent and independent action.
Experimental approaches:
.- Biochemical assays: enzymatic assays; ELISA; transporter function; Western blotting.
.- Pharmacological assays: receptor binding, G protein coupling.
.- Functional studies: behavioural (motor activity, pain tests, learning and memory,…)
.- Primary and cell line cultures: viability, NO and cytokine generation, migration, generation of reactive oxygen species.
.- Histological techniques and immunocytochemistry.
.- Stereotaxic lesions; intraventricular administration
