MANUELA G. LÓPEZ, MD, PhD
Professor of Pharmacology
Director of Instituto Teófilo Hernando for Drug Discovery
Universidad Autónoma de Madrid, Madrid
Our main interest is to understand which are the processes that underlie neurodegeneration with the aim of finding new targets to develop drugs to treat these diseases such as Alzheimer´s, Parkinson´s, stroke or depression. We are therefore focused on:
1. Target validation: Chronic diseases, such as the neurodegenerative, share common physiopathological mechanisms like oxidative stress, neuroinflammation, mitochondrial disfunction and autophagy impairment. In this scenario, we are investigating how interacting with different proteins that regulate the latter processes could provide positive outcomes in neurodegenerative conditions. We are currently focusing on cholinergic receptors (a7nAChR), melatonin receptors, the transcription factor NRF2 and enzymes implicated in oxidative stress such as hemoxygenase-1 or NADPH oxidases to regulate oxidative stress, neuroinflammation and autophagy to provide neuroprotection.
2. Drug development: As mentioned earlier, neurogenerative diseases have a complex and multifactorial pathogenesis, we are therefore interested in the design, synthesis and pharmacological evaluation of multitarget compounds for neurodegeneration. Within this research interest, we have recently created an in silico screening unit with the aim of finding new chemical structures for our targets of interest or the repurposing of drugs already in the market.
SELECTION OF PUBLICATIONS
1. I Casas, E. Geuss, P.W.M. Kleikers, S. Mencl, A. Herrmann, S.G. Meuth,M.G. Lopez, C. Kleinschnitz, H.H.H.W. Schmidt. (2017). NOX4-dependent neuronal autotoxicity and blood-brain barrier breakdown explain the superior sensitivity of the brain to ischemic damage. Proc. Nat. Acad. Sci. USA 114(46):12315-12320.
2. Rojo AI, Pajares M, García-Yagüe AJ, Buendia I, Van Leuven F, Yamamoto M, López MG, Cuadrado A. (2018). Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy. Redox Biol. 18:173-180.
3. Navarro E, Gonzalez-Lafuente L, Perez-Liebana I, Buendia I, López-Bernardo E, Sanchez, Ramos C, Prieto I, Cuadrado A, Satrustegui J, Cadenas S, Monsalve M, Lopez M.G. (2017) Heme-oxygenase I and PCG-1α regulate mitochondrial biogenesis via microglial activation of alpha7 nicotinic acetylcholine receptors using PNU282987. Antioxid Redox Signal. 27:93-105.
4. Teresa Ramos, Geoff Wells, Manuela G. López, Antonio Cuadrado, José Carlos Menéndez, and Rafael Leon. (2017). Discovery of the first dual GSK3β inhibitor / Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease. Sci Rep. 7:45701.
5. Buendia I,Parada E,Navarro E, Leon R, Negredo P,Egea J and Lopez MG. (2016) Subthreshold concentrations of melatonin and galantamine improves pathological AD hallmarks in hippocampal organotypic cultures. Molecular Neurobiology 53(5):3338-3348.
6. Navarro E, Buendia I, Parada E, León R, Jansen-Duerr p, Pircher h, Egea J and Lopez MG (2015) Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction. Biochemical Pharmacology 97. 473-481. 2015.
7. Parada E, Buendia I, Leon R, Negredo P, Romero A, Cuadrado A, Lopez MG and Egea J. (2014) Neuroprotective effect of melatonin against ischemia is partially mediated by alfa-7 nicotinic receptor modulation and HO-1 overexpression. J Pineal Res. 56(2):204-12.
8. Martin-de-Saavedra MD, Budini J, Cunha MP,Gomez-Rangel V, Lorrio S, del Barrio L, Lastres-Becker I, Parada E, Tordera RM, Rodrigues ALS, Cuadrado A and Lopez MG. (2013). Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. 38(10):2010-22.
9. Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, Soares MP, and Lopez MG. (2013) The microglial alpha-7 acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing HO-1 via Nrf2. Antioxidants & Redox Signaling. 19:1135-48.
10. Romero A, Egea J,Garcia AG and Lopez MG. (2010). Synergistic neuroprotective effect of combined concentrations of galantamine and melatonin against oxidative stress in SH-SY5Y neuroblastoma cells. Pineal Res. 49:141-148. 2010.
11. Parada E, Egea J, Romero A, del Barrio L, Garcia AG and Lopez MG (2010). Post-stress treatment with PNU282987 can rescue SH-SY5Y cells undergoing apoptosis via α7 nicotinic receptors linked to a Jak2/Akt/HO-1 signaling pathway. Free Radical Biology and Medicine. 49:1815-1821.