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Research has been conducted investigating the neuronal pathways responsible for the generation of chronic neuropathic pain, including the components of it in conditions such as chronic post-surgical pain, phantom limb pain, and cluster headaches. Forming part of the management of such conditions, capsaicin as a molecule has proven effective. This review has investigated the central nervous system modifications exhibited in such conditions and the pharmacological mechanisms of capsaicin relevant to this. The current paradigm for explaining topical capsaicin-induced analgesia is that TRPV1-mediated calcium ion influx induces calpain, in turn causing axonal ablation and functional defunctionalisation in the PNS (Peripheral Nervous System). Demonstrated through the analysis of existing data, this review demonstrates the changes seen in the CNS (Central Nervous System) in chronic neuropathic pain, as well as some of the evidence for capsaicin modulation on the CNS. Further supporting this, the specific molecular mechanisms of capsaicin-induced analgesia will also be explored, including the action of TRPV1, as well as discussing the further need for clinical research into this area of uncertainty due to the limited specific data with suitable parameters. Further research this review identified as potentially useful in this field included fMRI (functional Magnetic Resonance Imaging) studies, though more specific observational studies of patients who have already been administered capsaicin as a current treatment may prove helpful in studying the modification of the CNS in the long term.

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In this retrospective study, we aimed to evaluate the effects of the neurotrophic compound Cerebrolysin on executive, cognitive, and functional performance in patients with traumatic brain injury (TBI) with a highly severe disability level. A total of 44 patients were included in the study, with 33 patients in the control group and 11 patients in the interventional group who received intravenous infusions of 30 mL Cerebrolysin. Both groups received standard rehabilitation therapy following the rehabilitation protocol for patients with TBI at Hospital Clínico Mutual de Seguridad. Functional and cognitive scales were evaluated at baseline, at four months, and at the endpoint of the intervention therapy at seven months (on average). The results revealed a significant improvement in the Cerebrolysin-treated group compared to the control group. Specifically, patients who received Cerebrolysin showed a moderate residual disability and a significant reduction in the need for care. Concerning the promising results and considering the limitations of the retrospective study design, we suggest that randomized controlled studies be initiated to corroborate the positive findings for Cerebrolysin in patients with moderate to severe brain trauma.

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Prolonged infusion of a high dose of kynurenic acid (KYNA) reduces the myelin content in the rat spinal cord with preservation of the axonal integrity and without inducing an inflammatory response. We hypothesized that subdural infusion of a high concentration of KYNA can induce myelin loss in the optic nerves (ONs) of chickens. However, existing methods to deliver agents to the ON are inefficient, unlocalized and provide only acute exposure. Thus, we developed a surgical approach for sustained delivery of KYNA to the chicken ON. In brief, the novel surgical technique, which does not include excision of the extraocular muscles, involves incision of the skin and underlying fascial sheath to access the optic nerve within the muscle cone, implantation of a catheter in the dura of the optic nerve, the other end of which exits the orbit under the skin. The catheter runs under the skin near the lateral canthus, over the ears to the back of the neck, where a second incision is made to both implant the osmotic pump and to attach the catheter to the osmotic pump. India ink was used to confirm prolonged sustained administration to the optic nerves and across the chiasm. This surgical model was used to investigate KYNA's effect(s) on myelin loss in the ON. ONs of 7-day old chickens were infused with 50 mM KYNA or phosphate buffered saline (PBS) for seven days. Analysis of KYNA-infused contralateral ON g-ratios and protein levels indicated a reduction in myelin. These findings demonstrate the utility of our surgical approach for sustained delivery of KYNA into the ON and suggest a role for KYNA in modulating CNS myelination.

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Metastatic spinal melanoma is a rare and aggressive disease process with poor prognosis. We review the literature on metastatic spinal melanoma, focusing on its epidemiology, management, and treatment outcomes. Demographics of metastatic spinal melanoma are similar to those for cutaneous melanoma, and cutaneous primary tumors tend to be most common. Decompressive surgical intervention and radiotherapy have traditionally been considered mainstays of treatment, and stereotactic radiosurgery has emerged as a promising approach in the operative management of metastatic spinal melanoma. While survival outcomes for metastatic spinal melanoma remain poor, they have improved in recent years with the advent of immune checkpoint inhibition, used in conjunction with surgery and radiotherapy. New treatment options remain under investigation, especially for patients with disease refractory to immunotherapy. We additionally explore several of these promising future directions. Nevertheless, further investigation of treatment outcomes, ideally incorporating high-quality prospective data from randomized controlled trials, is needed to identify optimal management of metastatic spinal melanoma.

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Microphysiological system (MPS), a new technology for in vitro testing platforms, have been acknowledged as a strong tool for drug development. In the central nervous system (CNS), the blood‒brain barrier (BBB) limits the permeation of circulating substances from the blood vessels to the brain, thereby protecting the CNS from circulating xenobiotic compounds. At the same time, the BBB hinders drug development by introducing challenges at various stages, such as pharmacokinetics/pharmacodynamics (PK/PD), safety assessment, and efficacy assessment. To solve these problems, efforts are being made to develop a BBB MPS, particularly of a humanized type. In this study, we suggested minimal essential benchmark items to establish the BBB-likeness of a BBB MPS; these criteria support end users in determining the appropriate range of applications for a candidate BBB MPS. Furthermore, we examined these benchmark items in a two-dimensional (2D) humanized tricellular static transwell BBB MPS, the most conventional design of BBB MPS with human cell lines. Among the benchmark items, the efflux ratios of P-gp and BCRP showed high reproducibility in two independent facilities, while the directional transports meditated through Glut1 or TfR were not confirmed. We have organized the protocols of the experiments described above as standard operating procedures (SOPs). We here provide the SOPs with the flow chart including entire procedure and how to apply each SOP. Our study is important developmental step of BBB MPS towards the social acceptance, which enable end users to check and compare the performance the BBB MPSs.

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Primary familial brain calcification (PFBC) is an idiopathic pathology characterized by the development of calcific deposits in the supratentorial region such as telencephalon and diencephalon but also, in more extensive forms, in the cerebellum. Meningiomas are among the most common central nervous system (CNS) tumors generally related to a good prognosis. The simultaneous presence of intracerebral or extra-axial tumors and PFBC represents an exceedingly rare occurrence. A 72-year-old female patient was admitted to our department because of anoculogyric crisis followed by generalized seizures. She performed a brain CT scan which showed widespread hyperdensities in the paraventricular supratentorial region, basal ganglia and at the level of bilateral cerebellar dentate nuclei, characteristics of PFBC. Concomitant left frontal and smaller right temporal extra-axial lesions were identified and then confirmed in a brain MRI. The patient underwent a microsurgical resection of the lesion and subsequent histological examination reported a meningothelial meningioma (WHO Grade I). According to our literature review, this is the first paper that reports the coexistence of both intracranial meningiomas and PFBC. To date, it is not possible to provide an exact correlation between pathogenesis and genetic mechanism underlying this association.

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Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB.

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Activated microglia are divided into pro-inflammatory and anti-inflammatory functional states. In anti-inflammatory state, activated microglia contribute to phagocytosis, neural repair and anti-inflammation. Nrf2 as a major endogenous regulator in hematoma clearance after intracerebral hemorrhage (ICH) has received much attention. This study aims to investigate the mechanism underlying Nrf2-mediated regulation of microglial phenotype and phagocytosis in hematoma clearance after ICH. In vitro experiments, BV-2 cells were assigned to normal group and administration group (Nrf2-siRNA, Nrf2 agonists Monascin and Xuezhikang). In vivo experiments, mice were divided into 5 groups: sham, ICH + vehicle, ICH + Nrf2-/-, ICH + Monascin and ICH + Xuezhikang. In vitro and in vivo, 72 h after administration of Monascin and Xuezhikang, the expression of Nrf2, inflammatory-associated factors such as Trem1, TNF-α and CD80, anti-inflammatory, neural repair and phagocytic associated factors such as Trem2, CD206 and BDNF were analyzed by the Western blot method. In vitro, fluorescent latex beads or erythrocytes were uptaken by BV-2 cells in order to study microglial phagocytic ability. In vivo, hemoglobin levels reflect the hematoma volume. In this study, Nrf2 agonists (Monascin and Xuezhikang) upregulated the expression of Trem2, CD206 and BDNF while decreased the expression of Trem1, TNF-α and CD80 both in vivo and in vitro. At the same time, after Monascin and Xuezhikang treatment, the phagocytic capacity of microglia increased in vitro, neurological deficits improved and hematoma volume lessened in vivo. These results were reversed in the Nrf2-siRNA or the Nrf2-/- mice. All these results indicated that Nrf2 enhanced hematoma clearance and neural repair, improved neurological outcomes through enhancing microglial phagocytosis and alleviating neuroinflammation.

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Background: Although homeostasis of the cardiovascular system is regulated by the cerebral cortex via the autonomic nervous system, the role of abnormal brain functional connectivity (FC) networks in patients with cardiac dysfunction remains unclear. Here, we report thalamus-based FC alterations and their relationship with clinical characteristics in patients with coronary heart disease (CHD). Methods: We employed resting-state functional magnetic resonance imaging (rs-fMRI) to acquire imaging data in twenty-six patients with CHD alongside sixteen healthy controls (HCs). Next, we performed a thalamus-based FC analysis to profile abnormal FC patterns in the whole brain. Subsequently, the mean time series of the brain regions that survived in the FC analysis were used to determine correlations with clinical parameters in patients with CHD. Results: We found no statistically significant differences in demographic and clinical data between patients with CHD and HCs. Patients with CHD showed decreased FC patterns between bilateral thalami and left hemisphere, encompassing supplementary motor area, superior frontal gyrus, superior parietal gyrus, inferior parietal gyrus, middle cingulate cortex, lingual gyrus and calcarine sulcus. Conclusions: These findings not only have implications in clarifying the relationship between cerebral functional imbalance and cardiovascular system, but also provide valuable insights to guide future evaluation and management of cardiac autonomic regulation via the brain-heart axis.

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Anti-myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) associated disorder (MOGAD) is an immune-mediated central nervous system (CNS) inflammatory demyelinating disorder that has been widely recognized in recent years. It is distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which are separate disease spectrums. Here we report the case of a 5-year-old boy who was admitted for 3 days with fever, headache, and vomiting. Magnetic resonance imaging revealed abnormal hyperintensity in the left thalamus and positive serum IgM for M. pneumoniae. After treatment with azithromycin, the headache gradually disappeared, but paralysis and urinary retention occurred on the 6th day after admission. MRI re-examination showed that the original abnormal signal in the left thalamus was significantly weakened, but new abnormal signals appeared in the brain and cerebrospinal cord, and the serum MOG-IgG was positive. After treatment, the child has fully recovered and is still receiving follow-up care. We believe that this is a case of MOGAD in a child with a biphasic ADEM phenotype secondary to M. pneumoniae infection, which has potential value in elucidating the pathophysiology of MOGAD.

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Although well described in the current literature, Neurocysticercosis [NCC] remains an enigma when confronted by practitioners. This is in part due to the haphazard nature of the parasitic infection on the central nervous system [CNS]. These include single or multiple anatomic sites of infection, stage of parasitosis, and the resultant inflammatory response. As a result, NCC can present with a complex constellation of symptomatic presentations, making therapeutic regiments highly individualized. Despite intervention, other impediments may arise post-therapy due to the nature of the infection. We present a case of rapidly progressive symptomatic NCC that initially was successfully treated, however would eventually succumb to complications of ventriculitis.

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Background: Clerodendrum petasites, an herbal plant in Thailand, has been used for many years in folk medicine. However, scientific evidence regarding CNS safety pharmacology and antinociceptive activity of C. petasites (CP) has not yet been well characterized. Purpose: The present study aimed to assess the CNS safety pharmacology and antinociceptive and antiinflammatory effects of CP extract. Methods: The effect of CP extract on CNS safety pharmacology was assessed using LABORAS automated home cage monitoring and rotarod test. Its pharmacological activity was evaluated both in-vitro, and in-vivo using hot-plate, acetic acid-induced writhing, formalin, and carrageenan-induced paw edema models. Results and conclusion: CP extract significantly improved thermal and chemical nociceptive behaviors and acute inflammatory pain at all doses: 300, 600, and 1200 mg/kg, p.o. The antiinflammatory effect of CP extract in inflammatory pain models was comparable to the effect of positive control: indomethacin 10 mg/kg at all dose levels tested. Further, the CP extract at 600 mg/kg dose significantly inhibited 82.3% of carrageenan-induced total edema. In-vitro, CP extract at 12.5, 25, and 50 µg/mL concentrations significantly reduced the expression of LPS-induced nitric oxide, IL-6, and TNF-α expression in both RAW 264.7 macrophage and BV-2 microglial cell lines. In addition, CP extract did not show any potential effects on the CNS, indicated by no significant effects on motor coordination, spontaneous locomotor activity, general behaviors, and well-being compared to vehicle-treated mice (p > 0.05). Overall, the present study evidences the potential antinociceptive, antiinflammatory efficacies of CP extract with a favorable CNS safety profile.

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Extracellular vesicles (EVs) are a collective term for nanoscale or microscale vesicles secreted by cells that play important biological roles. Mesenchymal stem cells are a class of cells with the potential for self-healing and multidirectional differentiation. In recent years, numerous studies have shown that EVs, especially those secreted by mesenchymal stem cells, can promote the repair and regeneration of various tissues and, thus, have significant potential in regenerative medicine. However, due to the rapid clearance capacity of the circulatory system, EVs are barely able to act persistently at specific sites for repair of target tissues. Hydrogels have good biocompatibility and loose and porous structural properties that allow them to serve as EV carriers, thereby prolonging the retention in certain specific areas and slowing the release of EVs. When EVs are needed to function at specific sites, the EV-loaded hydrogels can stand as an excellent approach. In this review, we first introduce the sources, roles, and extraction and characterization methods of EVs and describe their current application status. We then review the different types of hydrogels and discuss factors influencing their abilities to carry and release EVs. We summarize several strategies for loading EVs into hydrogels and characterizing EV-loaded hydrogels. Furthermore, we discuss application strategies for EV-loaded hydrogels and review their specific applications in tissue regeneration and repair. This article concludes with a summary of the current state of research on EV-loaded hydrogels and an outlook on future research directions, which we hope will provide promising ideas for researchers.

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Dysfunctional top-down pain modulation is a hallmark of fibromyalgia (FM) and physical exercise is a cornerstone in FM treatment. The aim of this study was to explore the effects of a 15-week intervention of strengthening exercises, twice per week, supervised by a physiotherapist, on exercise-induced hypoalgesia (EIH) and cerebral pain processing in FM patients and healthy controls (HC). FM patients (n = 59) and HC (n = 39) who completed the exercise intervention as part of a multicenter study were examined at baseline and following the intervention. Following the exercise intervention, FM patients reported a reduction of pain intensity, fibromyalgia severity and depression. Reduced EIH was seen in FM patients compared to HC at baseline and no improvement of EIH was seen following the 15-week resistance exercise intervention in either group. Furthermore, a subsample (Stockholm site: FM n = 18; HC n = 19) was also examined with functional magnetic resonance imaging (fMRI) during subjectively calibrated thumbnail pressure pain stimulations at baseline and following intervention. A significant main effect of exercise (post > pre) was observed both in FM patients and HC, in pain-related brain activation within left dorsolateral prefrontal cortex and caudate, as well as increased functional connectivity between caudate and occipital lobe bordering cerebellum (driven by the FM patients). In conclusion, the results indicate that 15-week resistance exercise affect pain-related processing within the cortico-striatal-occipital networks (involved in motor control and cognition), rather than directly influencing top-down descending pain inhibition. In alignment with this, exercise-induced hypoalgesia remained unaltered.

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Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare chronic central-nervous-system inflammatory disorder that became known only recently, and the pathogenesis of CLIPPERS remains poorly understood. This report presents clinical and radiological features of a rare case: a young female patient who rapidly died of suspected CLIPPERS. Helpful multiparametric MRI diagnostic criteria are proposed that can help discriminate CLIPPERS from non-CLIPPERS pathologies. We reviewed clinical history, symptoms, quantitative data from brain multiparametric MRI before and after treatment, and histopathological data. Perfusion-weighted imaging revealed a decrease in regional cerebral blood flow by 31% and in cerebral blood volume by 64%, with a moderate increase in transit time and in time to peak by up to 23% in affected pontine and cerebral white matter. As estimated by diffusion tensor imaging, there was elevated density of tracts (n/mm2) and a decrease of fraction anisotropy (×10-3 mm/s2) in the patient's pons as compared to a healthy control: density of tracts = 13.5 vs 12.4 and fraction anisotropy = 0.32 vs 0.45, respectively. Macromolecular proton fraction values proved to be reduced (15.8% and 14.5% in the control, respectively) in the patient's cerebral peduncles by 3% and in the pons by 4.1% and in a periventricular white matter lesion by 6.4% (11.3% in the normal-looking contralateral hemisphere). Based on our findings, we argue that quantitative MRI techniques may be a valuable source of biomarkers and reliable diagnostic criteria and can shed light on the pathogenesis and exact nosological position of this disorder.

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COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

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The spleen is a key immune-related organ that plays a role in communication between the brain and the immune system through the brain-spleen axis and brain-gut-microbiota axis. However, how the gut microbiota affects spleen and brain function remains unclear. Here, we investigated whether microbiome depletion induced by administration of an antibiotic cocktail (ABX) affects spleen and brain function. Treatment with ABX for 14 days resulted in a significant decrease in spleen weight and significant alterations in splenic functions, including the percentage of neutrophils, NK cells, macrophages, and CD8+ T cells. Furthermore, ABX treatment resulted in the depletion of a large portion of the gut microbiota. Untargeted metabolomics analysis showed that ABX treatment caused alterations in the levels of certain compounds in the plasma, spleen, and brain. Moreover, ABX treatment decreased the expression of microglia marker Iba1 in the cerebral cortex. Interestingly, correlations were found between the abundance of different microbiome components and metabolites in various tissues, as well as splenic cell populations and spleen weight. These findings suggest that ABX-induced microbiome depletion and altered metabolite levels may affect spleen and brain function through the gut-microbiota-spleen-brain axis.