Innovative Insights into Traumatic Brain Injuries: Biomarkers and New Pharmacological Targets.

A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI's impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment.

Modulating Stress Proteins in Response to Therapeutic Interventions for Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative illness characterized by the degeneration of dopaminergic neurons in the substantia nigra, resulting in motor symptoms and without debilitating motors. A hallmark of this condition is the accumulation of misfolded proteins, a phenomenon that drives disease progression. In this regard, heat shock proteins (HSPs) play a central role in the cellular response to stress, shielding cells from damage induced by protein aggregates and oxidative stress. As a result, researchers have become increasingly interested in modulating these proteins through pharmacological and non-pharmacological therapeutic interventions. This review aims to provide an overview of the preclinical experiments performed over the last decade in this research field. Specifically, it focuses on preclinical studies that center on the modulation of stress proteins for the treatment potential of PD. The findings display promise in targeting HSPs to ameliorate PD outcomes. Despite the complexity of HSPs and their co-chaperones, proteins such as HSP70, HSP27, HSP90, and glucose-regulated protein-78 (GRP78) may be efficacious in slowing or preventing disease progression. Nevertheless, clinical validation is essential to confirm the safety and effectiveness of these preclinical approaches.

MicroRNAs and MAPKs: Evidence of These Molecular Interactions in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder known to be the leading cause of dementia worldwide. Many microRNAs (miRNAs) were found deregulated in the brain or blood of AD patients, suggesting a possible key role in different stages of neurodegeneration. In particular, mitogen-activated protein kinases (MAPK) signaling can be impaired by miRNA dysregulation during AD. Indeed, the aberrant MAPK pathway may facilitate the development of amyloid-beta (Aß) and Tau pathology, oxidative stress, neuroinflammation, and brain cell death. The aim of this review was to describe the molecular interactions between miRNAs and MAPKs during AD pathogenesis by selecting evidence from experimental AD models. Publications ranging from 2010 to 2023 were considered, based on PubMed and Web of Science databases. According to obtained data, several miRNA deregulations may regulate MAPK signaling in different stages of AD and conversely. Moreover, overexpressing or silencing miRNAs involved in MAPK regulation was seen to improve cognitive deficits in AD animal models. In particular, miR-132 is of particular interest due to its neuroprotective functions by inhibiting Aß and Tau depositions, as well as oxidative stress, through ERK/MAPK1 signaling modulation. However, further investigations are required to confirm and implement these promising results.

Regenerative Effects of Exosomes-Derived MSCs: An Overview on Spinal Cord Injury Experimental Studies.

Spinal cord injury (SCI) is a devastating condition usually induced by the initial mechanical insult that can lead to permanent motor and sensory deficits. At present, researchers are investigating potential therapeutic strategies to ameliorate the neuro-inflammatory cascade that occurs post-injury. Although the use of mesenchymal stromal/stem (MSCs) as a potential therapy in application to regenerative medicine promoted anti-inflammatory and neuroprotective effects, several disadvantages limit their use. Therefore, recent studies have reported the effects of exosomes-derived MSCs (MSC-EXOs) as an innovative therapeutic option for SCI patients. It is noteworthy that MSC-EXOs can maintain the integrity of the blood-spinal cord barrier (BSCB), promoting angiogenic, proliferative, and anti-oxidant effects, as well as immunomodulatory, anti-inflammatory, and antiapoptotic properties. Therefore, in this study, we summarized the preclinical studies reported in the literature that have shown the effects of MSC-EXOs as a new molecular target to counteract the devastating effects of SCI.

Cannabidiol Promotes Neuronal Differentiation Using Akt and Erk Pathways Triggered by Cb1 Signaling.

Recently, the scientific community has started to focus on the neurogenic potential of cannabinoids. The phytocompound cannabidiol (CBD) shows different mechanism of signaling on cannabinoid receptor 1 (CB1), depending on its concentration. In this study, we investigated if CBD may induce in vitro neuronal differentiation after treatment at 5 µM and 10 µM. For this purpose, we decided to use the spinal cord × neuroblastoma hybrid cell line (NSC-34) because of its proliferative and undifferentiated state. The messenger RNAs (mRNAs) expression profiles were tested using high-throughput sequencing technology and Western blot assay was used to determine the number of main proteins in different pathways. Interestingly, the treatment shows different genes associated with neurodifferentiation statistically significant, such as Rbfox3, Tubb3, Pax6 and Eno2. The CB1 signaling pathway is responsible for neuronal differentiation at 10 µM, as suggested by the presence of p-ERK and p-AKT, but not at 5 µM. A new correlation between CBD, neurodifferentiation and retinoic acid receptor-related orphan receptors (RORs) has been observed.

MiRNAs as Promising Translational Strategies for Neuronal Repair and Regeneration in Spinal Cord Injury.

Spinal cord injury (SCI) represents a devastating injury to the central nervous system (CNS) that is responsible for impaired mobility and sensory function in SCI patients. The hallmarks of SCI include neuroinflammation, axonal degeneration, neuronal loss, and reactive gliosis. Current strategies, including stem cell transplantation, have not led to successful clinical therapy. MiRNAs are crucial for the differentiation of neural cell types during CNS development, as well as for pathological processes after neural injury including SCI. This makes them ideal candidates for therapy in this condition. Indeed, several studies have demonstrated the involvement of miRNAs that are expressed differently in CNS injury. In this context, the purpose of the review is to provide an overview of the pre-clinical evidence evaluating the use of miRNA therapy in SCI. Specifically, we have focused our attention on miRNAs that are widely associated with neuronal and axon regeneration. "MiRNA replacement therapy" aims to transfer miRNAs to diseased cells and improve targeting efficacy in the cells, and this new therapeutic tool could provide a promising technique to promote SCI repair and reduce functional deficits.

Cannabinerol and NSC-34 Transcriptomic Analysis: Is the Dose Who Makes Neuronal Differentiation?

Cannabis sativa L. proved to be a source of several phytocompounds able to help patients facing different diseases. Moreover, these phytocompounds can help ameliorate general conditions and control certain unpleasant effects of diseases. Some cannabinoids, however, provided more benefits applicable to settings other than palliative care. Using the NSC-34 cell line, we evaluated the barely known phytocompound named cannabinerol (CBNR) at different doses, in order to understand its unique characteristics and the ones shared with other cannabinoids. The transcriptomic analysis suggests a possible ongoing neuronal differentiation, principally due to the activation of cannabinoid receptor 1 (CB1), to which the phosphorylation of serine-threonine protein kinase (Akt) followed, especially between 20 and 7.5 µM. The increase of Neurod1 and Map2 genes at 7.5 µM, accompanied by a decrease of Vim, as well as the increase of Syp at all the other doses, point toward the initiation of differentiation signals. Our preliminary results indicate CBNR as a promising candidate to be added to the list of cannabinoids with neuronal differentiation-enhancer properties. However, further studies are needed to confirm this initial insight.

The Role of Hypoxia in Improving the Therapeutic Potential of Mesenchymal Stromal Cells. A Comparative Study From Healthy Lung and Congenital Pulmonary Airway Malformations in Infants.

Mesenchymal stromal cells (MSCs) play an important role in the field of regenerative medicine thanks to their immunomodulatory properties and their ability to secrete paracrine factors. The use of MSCs has also been tested in children with congenital lung diseases inducing fibrosis and a decrease in lung function. Congenital malformations of the pulmonary airways (CPAM) are the most frequently encountered lung lesion that results from defects in early development of airways. Despite the beneficial properties of MSCs, interventions aimed at improving the outcome of cell therapy are needed. Hypoxia may be an approach aimed to ameliorate the therapeutic potential of MSCs. In this regard, we evaluated the transcriptomic profile of MSCs collected from pediatric patients with CPAM, analyzing similarities and differences between healthy tissue (MSCs-lung) and cystic tissue (MSCs-CPAM) both in normoxia and in cells preconditioned with hypoxia (0.2%) for 24 h. Study results showed that hypoxia induces cell cycle activation, increasing in such a way the cell proliferation ability, and enhancing cell anaerobic metabolism in both MSCs-lung and MSCs-CPAM-lung. Additionally, hypoxia downregulated several pro-apoptotic genes preserving MSCs from apoptosis and, at the same time, improving their viability in both comparisons. Finally, data obtained indicates that hypoxia leads to a greater expression of genes involved in the regulation of the cytoskeleton in MSCs-lung than MSCs-CPAM.

Aducanumab and Its Effects on Tau Pathology: Is This the Turning Point of Amyloid Hypothesis?

Alzheimer's disease (AD) is a neurodegenerative disorder affecting millions of people around the world. The two main pathological mechanisms underlying the disease are beta-amyloid (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of Tau proteins in the brain. Their reduction has been associated with slowing of cognitive decline and disease progression. Several antibodies aimed to target Aß or Tau in order to represent hope for millions of patients, but only a small number managed to be selected to participate in clinical trials. Aducanumab is a monoclonal antibody recently approved by the Food and Drug Administration (FDA), which, targeting (Aß) oligomers and fibrils, was able to reduce Aß accumulation and slow the progression of cognitive impairment. It was also claimed to have an effect on the second hallmark of AD, decreasing the level of phospho-Tau evaluated in cerebrospinal fluid (CSF) and by positron emission tomography (PET). This evidence may represent a turning point in the development of AD-efficient drugs.

Nrf2 Activation: Involvement in Central Nervous System Traumatic Injuries. A Promising Therapeutic Target of Natural Compounds.

Central nervous system (CNS) trauma, such as traumatic brain injury (TBI) and spinal cord injury (SCI), represents an increasingly important health burden in view of the preventability of most injuries and the complex and expensive medical care that they necessitate. These injuries are characterized by different signs of neurodegeneration, such as oxidative stress, mitochondrial dysfunction, and neuronal apoptosis. Cumulative evidence suggests that the transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial defensive role in regulating the antioxidant response. It has been demonstrated that several natural compounds are able to activate Nrf2, mediating its antioxidant response. Some of these compounds have been tested in experimental models of SCI and TBI, showing different neuroprotective properties. In this review, an overview of the preclinical studies that highlight the positive effects of natural bioactive compounds in SCI and TBI experimental models through the activation of the Nrf2 pathway has been provided. Interestingly, several natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response against CNS trauma. Therefore, some of these compounds could represent promising therapeutic strategies for these pathological conditions.