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[This corrects the article DOI: 10.3389/fphys.2023.1217815.].

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Mitochondrial dysfunction is a central event in the pathogenesis of several degenerative brain disorders. It entails fission and fusion dynamics disruption, progressive decline in mitochondrial clearance, and uncontrolled oxidative stress. Many therapeutic strategies have been formulated to reverse these alterations, including replacing damaged mitochondria with healthy ones. Spontaneous mitochondrial transfer is a naturally occurring process with different biological functions. It comprises mitochondrial donation from one cell to another, carried out through different pathways, such as the formation and stabilization of tunneling nanotubules and Gap junctions and the release of extracellular vesicles with mitochondrial cargoes. Even though many aspects of regulating these mechanisms still need to be discovered, some key enzymatic regulators have been identified. This review summarizes the current knowledge on mitochondrial dysfunction in different neurodegenerative disorders. Besides, we analyzed the usage of mitochondrial transfer as an endogenous revitalization tool, emphasizing the enzyme regulators that govern this mechanism. Going deeper into this matter would be helpful to take advantage of the therapeutic potential of mitochondrial transfer.

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OBJECTIVE: To develop N-(levodopa) chitosan derivatives through click chemistry to study their effect in brain cells.Significance: This study presents a proof-of-concept that macromolecules such as N-(Levodopa) chitosan derivatives traverse brain cell membranes and induce biomedical functionalities. METHODS: Through click chemistry, we developed N-(levodopa) chitosan derivatives. They were physically and chemically characterized by FT-IR, 1H-NMR, TGA and Dynamic Light Scattering analyses. Solution and nanoparticles of N-(levodopa) chitosan derivatives were tested in primary cell cultures from the postnatal rat olfactory bulb, substantia nigra and corpus callosum. Ca2+ imaging and UPLC experiments were used to investigate if the biomaterial modulated the brain cell physiology. RESULTS: N-(levodopa) chitosan derivatives induced intracellular Ca2+ responses in primary cell cultures of the rat brain. UPLC experiments indicated that levodopa attached to chitosan was converted into dopamine by brain cells. CONCLUSION: The present study shows that N-(levodopa) chitosan may be useful to develop new treatment strategies, which could serve as molecular reservoirs of biomedical drugs to treat degenerative disorders of the nervous system.

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The renin-angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin-I-converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti-inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness.

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Brain functions are influenced by the presence, activity, and metabolism of the gut microbiota through the gut-microbiota-brain (GMB) axis. The consumption of a fiber-rich diet increases the content of short-chain fatty acids (SCFAs) from bacterial fermentation in the colon. Among SCFAs, butyrate stands out because of its wide array of biological functions, such as ability to influence brain functions. Pharmacologically, sodium butyrate (NaB) regulates gene expression in the brain, where it has several beneficial effects ranging from neurodegenerative diseases to behavioral disorders through inhibitors of histone deacetylases (HDACis). In this context, we review the mechanisms of action of the two types of butyrate on brain functions, with an emphasis on the epigenetic approach. Both types of butyrate are potentially interesting for the prevention and adjuvant therapy of neurological and psychological disorders due to their neuroprotective functions. However, further studies are needed to investigate the possible neuroepigenetic effects of butyrate derived from bacterial fermentation.

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment. Curcumin-loaded mesoporous silica nanoparticles (MSN-CCM) can overcome the drawbacks related to the free curcumin (CCM) clinical application, such as water insolubility and low bioavailability, besides acting over the main causes associated to AD. A thermo-responsive hydrogel is an interesting approach for facilitating the administration of the nanosystem via a nasal route, as well as for overcoming mucociliary clearance mechanisms. In light of this, MSN-CCM were dispersed in the hydrogel and evaluated through in vitro and in vivo assays. The MSNs and MSN-CCM were successfully characterized by physicochemical analysis and a high value of the CCM encapsulation efficiency (EE%, 87.70 ± 0.05) was achieved. The designed thermo-responsive hydrogel (HG) was characterized by rheology, texture profile analysis, and ex vivo mucoadhesion, showing excellent mechanical and mucoadhesive properties. Ex vivo permeation studies of MSN-CCM and HG@MSN-CCM showed high permeation values (12.46 ± 1.08 and 28.40 ± 1.88 µg cm-2 of CCM, respectively) in porcine nasal mucosa. In vivo studies performed in a streptozotocin-induced AD model confirmed that HG@MSN-CCM reverted the cognitive deficit in mice, acting as a potential formulation in the treatment of AD.

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Shotgun proteomics based in mass spectrometry has been extensively utilized to investigate biological samples for basic and applied research in the clinical field to elucidate changes in the molecular mechanisms caused by diseases. There is still a great lack of information about the molecular mechanisms and the origins of most brain disorders, which makes shotgun proteomics an interesting tool in the study of these diseases. A wide range of samples can be used to study such diseases, such as cerebrospinal fluid, central nervous system cells, and brain tissue via postmortem analysis. As such, different protein extraction methods must be applied to achieve the best results for each sample type. The lysis buffer, digestion protocol, and peptide purification steps chosen prior to liquid chromatography-mass spectrometry analyses are essential to obtain reliable proteomic datasets. For this reason, the availability of a list with a variety of methods and a description of the pros and cons for each one has been compiled and elaborated upon. This review presents several methods for protein extraction, protein digestion, and sample cleanup with a focus on shotgun proteomics via mass spectrometry and a further focus on studying brain disorders.

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Protein phosphatases are major regulators of signal transduction and they are involved in key cellular mechanisms such as proliferation, differentiation, and cell survival. Here we focus on one class of protein phosphatases, the type IIA Receptor-type Protein Tyrosine Phosphatases (RPTPs), or LAR-RPTP subfamily. In the last decade, LAR-RPTPs have been demonstrated to have great importance in neurobiology, from neurodevelopment to brain disorders. In vertebrates, the LAR-RPTP subfamily is composed of three members: PTPRF (LAR), PTPRD (PTPδ) and PTPRS (PTPσ), and all participate in several brain functions. In this review we describe the structure and proteolytic processing of the LAR-RPTP subfamily, their alternative splicing and enzymatic regulation. Also, we review the role of the LAR-RPTP subfamily in neural function such as dendrite and axon growth and guidance, synapse formation and differentiation, their participation in synaptic activity, and in brain development, discussing controversial findings and commenting on the most recent studies in the field. Finally, we discuss the clinical outcomes of LAR-RPTP mutations, which are associated with several brain disorders.

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Neuropeptides acting on specific cell membrane receptors of the G protein-coupled receptor (GPCR) superfamily regulate a range of important aspects of nervous and neuroendocrine function. Gastrin-releasing peptide (GRP) is a mammalian neuropeptide that binds to the GRP receptor (GRPR, BB2). Increasing evidence indicates that GRPR-mediated signaling in the central nervous system (CNS) plays an important role in regulating brain function, including aspects related to emotional responses, social interaction, memory, and feeding behavior. In addition, some alterations in GRP or GRPR expression or function have been described in patients with neurodegenerative, neurodevelopmental, and psychiatric disorders, as well as in brain tumors. Findings from preclinical models are consistent with the view that the GRPR might play a role in brain disorders, and raise the possibility that GRPR agonists might ameliorate cognitive and social deficits associated with neurological diseases, while antagonists may reduce anxiety and inhibit the growth of some types of brain cancer. Further preclinical and translational studies evaluating the potential therapeutic effects of GRPR ligands are warranted.

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Brain disorders account for more than 34% of the global burden of disease, crippling nations by decreasing their "mental capital"-with greater effect in developing countries. Early detection is the key to their management, but establishing such programmes seems nearly impossible due to the high prevalence of the dysfunctions as compared with the high cost of neuroimaging devices. Thus, at first sight, the research of the Decade of the Brain and the international Human Brain Mapping Project might seem to be condemned to benefit only a small elite. Cuba has shown that is not so by using neurotechnology for the last 3 decades to implement stratified active screening programmes for brain disorders at the population level. This experience has shown that, by the transformation of health indicators, an appropriate use of technology can be integrated with attention to the population at the primary levels of both health care and education. An essential component of neurotechnology is neuroinformatics, which-like its counterpart bioinformatics-combines databases, analysis tools, and theoretical models to craft tools for early disease diagnosis and management. Much work remains to be done and will depend critically on south-south cooperation to solve problems for countries with similar situations.