Dr. Padovan-Neto research is focused on determining the role of nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMPin Parkinson's disease (PD, focused on L-DOPA-induced dyskinesia) and Huntington's disease (HD).

PD is a neurodegenerative disorder that affects1% of people over the age of 60. L-DOPA therapy may ameliorate motor symptoms associated with PD, but loses effectiveness with time and produces debilitating side effects that include motor complications called L-DOPA-induced dyskinesia (LID). Once they have become established, LID occurs after every L-DOPA administration. Motor complications occur in about 50% of PD patients undergoing L-DOPA therapy for 5 years and the incidence increases over the years.  Therefore, a fundamental approach to PD treatment is to identify novel therapies that will avoid dyskinesia induction. Non-dopaminergic mechanisms are emerging as new therapeutic targets for PD. For example nitric oxide synthase (NOS) inhibitors and cyclic nucleotides (cAMP/cGMP) metabolizing phosphodiesterases (PDEs) inhibitors are one promising antidyskinetic co-therapy. Our studies have revealed that targeting these systems is a powerful preclinical approach for studying the influence of NO-cGMP signaling pathways in LID.

HD is an autosomal dominant neurodegenerative disorder caused by abnormal expansion in CAG trinucleotide repeats within the gene encoding for the huntingtin protein. Recent studies indicate that the synthesis and/or catabolism of cyclic nucleotides in striatal neurons are likely to be perturbed in preclinical models and patients with HD. Striatal medium spiny neurons contain very high levels of cyclic nucleotide PDEs, key enzymes involved in the metabolism of cAMP/cGMP. Our studies focus on the impact of a selective inhibition of PDE10A enzyme on neuronal activity measured in the striatum of rodent models of HD.

1.   Padovan-Neto, F.E., Echeverry, M.B., Tumas,V., Del-Bel, E.A. (2009). Nitric oxide synthase inhibition attenuates L-DOPA-induced dyskinesias in a rodent model of Parkinson's disease. Neuroscience, 159(3):927-935.

2.    Padovan-Neto, F.E., Echeverry, M.B., Chiavegatto, S., Del-Bel, E. (2011). Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats. Frontiers in Systems Neuroscience, 5:40. PMCID: PMC3114204

3.    Mitkovski, M., Padovan-Neto, F.E., Raisman-Vozari, R., Ginestet, L., da-Silva, C.A., Del-Bel, E.A. (2012).Investigations into potential extrasynaptic communication between the dopaminergic and nitrergic systems. Frontiers in Physiology, 3:372. PMCID:PMC3457048

4.   Padovan-Neto, F.E., Ferreira, N.R., de Oliveira-Tavares,D., de Aguiar, D., da Silva, C.A., Raisman-Vozari, R., Del Bel, E. (2013).Anti-dyskinetic effect of the neuronal nitric oxide synthase inhibitor is linked to decrease of FosB/deltaFosB expression. Neuroscience Letters, 541:126-131.

5.    Del-Bel.E., Padovan-Neto, F.E., Szawka, R.E., da-Silva, C.A., Raisman-Vozari, R., Anselmo-Franci, J., Romano-Dutra, A.C., Guimaraes, F.S. (2014). Counteraction by nitric oxide synthase inhibitor of neurochemical alterations of dopaminergic system in 6-OHDA-lesioned rats under L-DOPA treatment. Neurotoxicity Research,25(1):33-44.

6.    Padovan-Neto, F.E., Cavalcanti-Kiwiatkoviski,R., Carolino, R.O., Anselmo-Franci, J., Del Bel, E. (2015). Effects of prolonged neuronal nitric oxide synthase inhibition on the development and expression of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. Neuropharmacology, 89:87-99.

7.     Padovan-Neto, F.E., Sammut, S., Chakroborty, S., Dec, A.M., Threlfell, S., Campbell, P.W., Mudrakola, V., Harms, J.F., Schmidt, C.J., West, A.R. (2015). Facilitation of corticostriatal transmission following pharmacological inhibition of striatal phosphodiesterase 10A: role of nitric oxide-soluble guanylyl cyclase-cGMP signaling pathways. Journal of Neuroscience, 35(14):5781-5791. PMID: 25855188

8.    Bortolanza, M.,Padovan-Neto, F.E., Cavalcanti-Kiwiatkoski, R., Dos Santos-Pereira, M., Mitkovski, M., Raisman-Vozari, R., Del-Bel, E. (2015). Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced by L-DOPA? Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 370(1672). PMID: 26009769