Pharmacological neuroprotection in neurodegenerative disease and stroke
Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and stroke have a terrible cost, in both financial and human terms. Treatments for neurodegenerative diseases (NDDs) are destined to become the most important health problem for this generation. To date, no therapeutic strategy has been effective and millions have been invested in failed therapeutic trials.
There is therefore a very urgent need to identify innovative therapeutic strategies that could protect or rescue vulnerable neurons in these terrible diseases. Our research group is interested in developing pre-clinical in vitro and in vivo models that may be more relevant to NDDs in human pathology; and in evaluating new therapies for NDDs based on new targets involving control of redox balance and neuroinflammation. We are also interested in the combined therapy approach using commercial drugs with complementary mechanisms of action: this strategy works well in diseases such as cancer and AIDS, and we believe it could become a useful approach in future treatment of NDDs.
We are also interested in finding markers for early diagnosis, tracking neurodegenerative disease progression and measuring responses to therapy. Predicting outcome after ischaemic stroke is important for clinicians, patients and researchers. We are therefore attempting to define protein changes associated with acute ischaemic brain damage, which could help us identify new biomarker candidates for stroke prognosis.
When it comes to chemical medicine, our group is developing new chemical entities as potential drugs for the treatment of neurodegenerative diseases. Our approach is based on the use of multi-target ligands, i.e. the design, synthesis and biological evaluation of a molecule that integrates two or more activities for targets involved in neurodegeneration, such as the mitochondrial sodium/potassium exchanger, the calcium-1 homeostasis modulator or 2A phosphatase, new Nrf2 inducers combined with the “scavenger” effect, the inhibition of several enzymes related to neurological disorders and agonists of nicotinic acetylcholine receptors; thus determining the actual contribution of these targets to the pathophysiological pathways of neuronal death/survival.
Manuela García López
Universidad Autónoma de Madrid-Instituto Teófilo Hernando
| Other team members:
García López, Manuela (Coordinadora). Desarrollo de fármacos activadores de activadores de NRF2 para terapias innovadoras de la enfermedad de Alzheimer. B2017/BDM-3827. Comunidad de Madrid. 2018-2020.
Del Barrio L, Martín-de-Saavedra MD, Romero A, Parada E, Egea J, Avila J, McIntosh JM, Wonnacott S, López MG. Neurotoxicity induced by okadaic acid in the human neuroblastoma SH-SY5Y line can be differentially prevented by α7 and β2* nicotinic stimulation. Toxicol Sci 2011. 123:193-205. FI: 4.652 (Q1). PMID: 21715663. DOI: 10.1093/toxsci/kfr163.
Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, Soares MP, López MG. The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2. Antioxid Redox Signal 2013. 10:1135-1148. FI: 7.667 (Q1). PMID: 23311871. DOI: 10.1089/ars.2012.4671.
Martín-de-Saavedra MD1, Budni J, Cunha MP, Gómez-Rangel V, Lorrio S, Del Barrio L, Lastres-Becker I, Parada E, Tordera RM, Rodrigues AL, Cuadrado A, López MG. Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology 2013. 38:2010-2022. FI: 5.591 (Q1). PMID: 23623252. DOI: 10.1016/j.psyneuen.2013.03.020.
Parada E, Buendia I, León R, Negredo P, Romero A, Cuadrado A, López MG, Egea J. Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression. J Pineal Res 2014. 56:204-212. FI: (Q). PMID: 24350834. DOI: 10.1111/jpi.12113.