Simvastatin is delivered to the brain by high-strength intranasal cationic SMEDDS and nanoemulsions.

The repurposing of statins as neuroprotective agents and/or anti-brain tumor drugs is limited by challenges in brain bioavailability and systemic off-target effects. Therefore, improved and targeted delivery of statins to the brain is necessary. This study aimed to develop a high-strength liquid formulation of the poorly soluble prodrug simvastatin for intranasal administration, as a strategy to achieve high brain concentrations of the prodrug and/or its active form, tenivastatin.

Preconditioning of MSCs for Acute Neurological Conditions: From Cellular to Functional Impact-A Systematic Review.

This systematic review aims to gather evidence on the mechanisms triggered by diverse preconditioning strategies for mesenchymal stem cells (MSCs) and their impact on their potential to treat ischemic and traumatic injuries affecting the nervous system. The 52 studies included in this review report nine different types of preconditioning, namely, manipulation of oxygen pressure, exposure to chemical substances, lesion mediators or inflammatory factors, usage of ultrasound, magnetic fields or biomechanical forces, and culture in scaffolds or 3D cultures. All these preconditioning strategies were reported to interfere with cellular pathways that influence MSCs' survival and migration, alter MSCs' phenotype, and modulate the secretome and proteome of these cells, among others.

Endogenous GDNF Is Unable to Halt Dopaminergic Injury Triggered by Microglial Activation.

Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson's disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses.

"Lipopolysaccharide-induced animal models for neuroinflammation - An overview.".

Neuroinflammation is a pathological mechanism contributing to neurodegenerative diseases. For in-depth studies of neuroinflammation, several animal models reported reproducing behavioral dysfunctions and cellular pathological mechanisms induced by brain inflammation. One of the most popular models of neuroinflammation is the one generated by lipopolysaccharide exposure.

Secretome as a Tool to Treat Neurological Conditions: Are We Ready?

Due to their characteristics, mesenchymal stem cells (MSCs) are considered a potential therapy for brain tissue injury or degeneration. Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings.

Contribution of glial cells to the neuroprotective effects triggered by repetitive magnetic stimulation: a systematic review.

Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases, and although most studies focus on its effects on neuronal cells, the contribution of non-neuronal cells to the improvement triggered by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested. To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases, Web of Science and PubMed were searched for the effects of high-frequency-repetitive transcranial magnetic stimulation, low-frequency-repetitive transcranial magnetic stimulation, intermittent theta-burst stimulation, continuous theta-burst stimulation, or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells. A total of 52 studies were included.

Hypothermia Does Not Boost the Neuroprotection Promoted by Umbilical Cord Blood Cells in a Neonatal Hypoxia-Ischemia Rat Model.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term disability in the perinatal period. Currently, therapeutic hypothermia is the standard of care for this condition with modest efficacy and strict enrollment criteria. Therapy with umbilical cord blood cells (UCBC) has come forward as a strong candidate for the treatment of neonatal HIE, but no preclinical studies have yet compared the action of UCBC combined with hypothermia (HT) with the action of each therapy by itself.

High-frequency repetitive magnetic stimulation rescues ischemia-injured neurons through modulation of glial-derived neurotrophic factor present in the astrocyte's secretome.

Due to its ability to improve the most frequent clinical sequelae left by ischemia, repetitive transcranial magnetic stimulation has been considered a promising therapeutic strategy for stroke. Those improvements are associated with changes in neurons and their synaptic liaisons. However, the hypothesis that this technique modulates astrocytes, potentiating their neuroprotective capabilities, was also raised.

In Vitro Model for Ischemic Stroke: Functional Analysis of Vascular Smooth Muscle Cells.

The Neurovascular Unit (NVU) is formed by vascular and neural cells controlling the cerebral hyperaemia. All the components are anatomically and functionally linked to each other, resulting in a highly efficient regulation of the cerebral blood flow, which, when interrupted, can lead to stroke. An ischemic stroke (IS) is the most common type of stroke with high rates of morbidity, mortality and disability.

Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy: A Systematic Review of Preclinical Studies.

Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of mortality and morbidity in the perinatal period. This condition results from a period of ischemia and hypoxia to the brain of neonates, leading to several disorders that profoundly affect the daily life of patients and their families. Currently, therapeutic hypothermia (TH) is the standard of care in developing countries; however, TH is not always effective, especially in severe cases of HIE.

Astrocytes contribute to the neuronal recovery promoted by high-frequency repetitive magnetic stimulation in in vitro models of ischemia.

After decades of effort, there are no effective clinical treatments to induce the recovery of ischemia-injured tissues, and among the several strategies that have been explored, repetitive transcranial magnetic stimulation has proven to be one of the most promising, with beneficial effects in limb motor function, aphasia, hemispatial neglect, or dysphagia. Despite the clinical evidences, little is known about the mechanisms underlying those effects. The present study aimed to explore the cellular and molecular effects of high-frequency repetitive magnetic stimulation (HF-rMS) on an in vitro model of ischemia.

A Cell Culture Model for Studying the Role of Neuron-Glia Interactions in Ischemia.

Ischemic stroke is a clinical condition characterized by hypoperfusion of brain tissue, leading to oxygen and glucose deprivation, and the consequent neuronal loss. Numerous evidence suggests that the interaction between glial and neuronal cells exert beneficial effects after an ischemic event. Therefore, to explore potential protective mechanisms, it is important to develop models that allow studying neuron-glia interactions in an ischemic environment.

Characterization of culture from smooth muscle cells isolated from rat middle cerebral arteries.

Although human brain represents only 2% of the body mass, it uses around 20 % of the organism energy. Due to the brain's limited energy storage, the oxygen and glucose necessary to support brain functions depends on the correct blood supply. The main components of the arteries are smooth muscle cells, which are considered the main regulators of vascular tone and blood flow distribution.

A different vision of translational research in biomarker discovery: a pilot study on circulatory mitochondrial proteins as Parkinson's disease potential biomarkers.

Background: The identification of circulating biomarkers that closely correlate with Parkinson's Disease (PD) has failed several times in the past. Nevertheless, in this pilot study, a translational approach was conducted, allowing the evaluation of the plasma levels of two mitochondrial-related proteins, whose combination leads to a robust model with potential diagnostic value to discriminate the PD patients from matched controls.

Methods: The proposed translational approach was initiated by the analysis of secretomes from cells cultured under control or well-defined oxidative stress conditions, followed by the identification of proteins related to PD pathologic mechanisms that were altered between the two states.

Astrocyte signaling impacts the effects of human bone marrow mesenchymal stem cells secretome application into the hippocampus: A proliferation and morphometrical analysis on astrocytic cell populations.

The central nervous system (CNS) has a limited auto-regeneration capacity, which makes it challenging for the development of new therapies. Previous studies from our lab have demonstrated the applicability of human bone marrow mesenchymal stem cells (hBM-MSCs) secretome as a possible therapeutic tool for CNS. Astrocytes, glial cells present in all brain regions, are important players in brain function through their vast influence in extracellular homeostasis, neuro-vascular regulation, synaptic modulation and neurogenesis.

The Neurovascular Unit: Focus on the Regulation of Arterial Smooth Muscle Cells.

The neurovascular unit is a physiological unit present in the brain, which is constituted by elements of the nervous system (neurons and astrocytes) and the vascular system (endothelial and mural cells). This unit is responsible for the homeostasis and regulation of cerebral blood flow. There are two major types of mural cells in the brain, pericytes and smooth muscle cells.

G protein-coupled estrogen receptor activates cell type-specific signaling pathways in cortical cultures: relevance to the selective loss of astrocytes.

Selective activation of the G protein-coupled estrogen receptor has been proposed to avoid some of the side effects elicited by the activation of classical estrogen receptors α and β. Although its contribution to neuroprotection triggered by estradiol in brain disorders has been explored, the results regarding ischemic stroke are contradictory, and currently, there is no consensus on the role that this receptor may play. The present study aimed to investigate the role of GPER in the ischemic insult.

GPER activation is effective in protecting against inflammation-induced nigral dopaminergic loss and motor function impairment.

Increasing evidence suggest that excessive inflammatory responses from overactivated microglia play a critical role in Parkinson's disease (PD), contributing to, or exacerbating, nigral dopaminergic (DA) degeneration. Recent results from our group and others demonstrated that selective activation of G protein-coupled estrogen receptor (GPER) with the agonist G1 can protect DA neurons from 1-methyl-4-phenylpyridinium (MPP) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxins. However, it is not known whether modulation of microglial responses is one of the mechanisms by which G1 exerts its DA neuroprotective effects.

Impact of Astrocytes on the Injury Induced by In Vitro Ischemia.

Cell cultures are characterized by their simplicity, controllability, and ability to provide detailed basic information on how a particular cell population responds to specific stimuli or insult. These characteristics led to their extensive application in the study of molecular interactions and represent a valuable tool in the study of different pathologies. However, due to the lack of interactions between the different components that form an in vivo system, the results obtained in pure cell cultures not always translate what occurs in vivo.

Role of Neurotrophic Factors in Parkinson's Disease.

Parkinson's disease is an age-associated progressive neurodegenerative disorder that has gained crescent social and economic impact due to the aging of the western society. All current therapies are symptomatic and fail to reverse or halt the progression of dopaminergic neurons loss. The discovery of the capability of neurotrophic factors to protect these neurons lead numerous research groups to focus their efforts in developing therapies aiming at promoting the control of Parkinson´s disease through the delivery of neurotrophic factors to the brain or by boosting their endogenous levels.

GPER: A new tool to protect dopaminergic neurons?

Parkinson's disease (PD) is characterized by a selective degeneration of nigrostriatal dopaminergic pathway. Epidemiological studies revealed a male predominance of the disease that has been attributed to the female steroid hormones, mainly the estrogen. Estrogen neuroprotective effects have been shown in several studies, however the mechanisms responsible by these effects are still unclear.

Retinoic acid-loaded polymeric nanoparticles induce neuroprotection in a mouse model for Parkinson's disease.

Retinoic acid (RA) plays an important role in the commitment, maturation and survival of neural cells. Recently, RA was pointed as a therapeutic option for some neurodegenerative diseases, including Parkinson's disease (PD). The administration of RA has been defying, and in this sense we have previously developed novel RA-loaded polymeric nanoparticles (RA-NPs) that ensure the efficient intracellular transport and controlled release of RA.

STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD.