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The numerous efforts invested in the identification of biomarkers for neurodegenerative and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, are justified because these disorders affect several million people worldwide. Although genetic implications and the role of the environment have been shown in the progression of those disorders, together with anatomical and neurochemical characteristics, an integrated view of the biochemical pathways involved in the pathophysiology of these disorders is still being unraveled. The use of proteomic methodologies, molecular mechanisms and potential biomarker candidates for the prognosis, diagnosis and treatment of brain disorders has been discussed. Similar methodologies can be applied for the large-scale identification of peptides to characterize the brain peptidome with the aim of closing the knowledge gaps that remain. Brain cells contain a large number of peptides that play pivotal roles in cell communication. Peptidome studies have recently identified more than 800 peptides in mouse brain extracts, with half of them derived from secretory pathways. For example, several of these peptides were identified as bioactive neuropeptides that activate G-coupled receptors. In addition, intracellular peptides derived from nuclear, cytosolic and mitochondrial proteins have been identified, including the hemopressins, which act with high selectivity for the cannabinoid receptor type 1. Considering the importance of peptides in cell signaling, the present review intends to discuss the recent findings of the peptidome field, focusing on Parkinson's disease and schizophrenia. New approaches to evaluate intracellular peptide signaling at the protein-protein interaction level and the future perspectives of peptides as intracellular modulators of signal transduction are explored.

We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN) of wild-type (wt) mice after PD induction. Gp91(phox-/-) 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA) neurons in the SN of wt mice. In gp91(phox-/-) 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91(phox-/-) 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91(phox-/-)-lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91(phox-/-) 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91(phox-/-) 6-OHDA lesioned mice, a likely mechanism whereby gp91(phox-/-) 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.

Several lines of investigation have implicated oxidative stress in Parkinson's disease (PD) pathogenesis, but the mechanisms involved are still unclear. In this study, we characterized the involvement of NADPH oxidase (Nox), a multisubunit enzyme that catalyzes the reduction of oxygen, in the 6-hydroxydopamine- (6-OHDA-) induced PD mice model and compared for the first time the effects of this neurotoxin in mice lacking gp91(phox-/-), the catalytic subunit of Nox2, and pharmacological inhibition of Nox with apocynin. Six-OHDA induced increased protein expression of p47(phox), a Nox subunit, in striatum. gp91(phox-/-) mice appear to be completely protected from dopaminergic cell loss, whereas the apocynin treatment conferred only a limited neuroprotection. Wt mice treated with apocynin and gp91(phox-/-) mice both exhibited ameliorated apomorphine-induced rotational behavior. The microglial activation observed within the striatum and the substantia nigra pars compacta (SNpc) of 6-OHDA-injected Wt mice was prevented by apocynin treatment and was not detected in gp91(phox-/-) mice. Apocynin was not able to attenuate astrocyte activation in SN. The results support a role for Nox2 in the 6-OHDA-induced degeneration of dopaminergic neurons and glial cell activation in the nigrostriatal pathway and reveal that no comparable 6-OHDA effects were observed between apocynin-treated and gp91(phox-/-) mice groups.

Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson's and Alzheimer's diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of São Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.