Long-COVID impacts taste and olfactory in individuals with substance use disorder: A retrospective cohort study from the TriNetX US Collaborative Networks.

Substance use disorder (SUD) exacerbates the impact of Long-COVID, particularly increasing the risk of taste and olfactory disorders. Analyzing retrospective cohort data from TriNetX and over 33 million records (Jan 2020-Dec 2022), this study focused on 1,512,358 participants, revealing that SUD significantly heightens the likelihood of experiencing taste disturbances and anosmia in Long-COVID sufferers. Results indicated that individuals with SUD face a higher incidence of sensory impairments compared to controls, with older adults and women being particularly vulnerable. Smokers with SUD were found to have an increased risk of olfactory and taste dysfunctions. The findings underscore the importance of early screening, diagnosis, and interventions for Long-COVID patients with a history of SUD, suggesting a need for clinicians to monitor for depression and anxiety linked to sensory dysfunction for comprehensive care.

CHST11-modified chondroitin 4-sulfate as a potential therapeutic target for glioblastoma.

Aberrant chondroitin sulfate (CS) accumulation in glioblastoma (GBM) tissue has been documented, but the role of excessive CS in GBM progression and whether it can be a druggable target are largely unknown. The aim of this study is to clarify the biological functions of CHST11 in GBM cells, and evaluate therapeutic effects of blocking CHST11-derived chondroitin 4-sulfate (C4S). We investigated the expression of CHST11 in glioma tissue by immunohistochemistry, and analyzed CHST11 associated genes using public RNA sequencing datasets. The effects of CHST11 on aggressive cell behaviors have been studied in vitro and in vivo. We demonstrated that CHST11 is frequently overexpressed in GBM tissue, promoting GBM cell mobility and modulating C4S on GBM cells. We further discovered that CSPG4 is positively correlated with CHST11, and CSPG4 involved in CHST11-mediated cell invasiveness. In addition, GBM patients with high expression of CHST11 and CSPG4 have a significantly shorter survival time. We examined the effects of treating C4S-specific binding peptide (C4Sp) as a therapeutic agent in vitro and in vivo. C4Sp treatment attenuated GBM cell invasiveness and, notably, improved survival rate of orthotopic glioma cell transplant mice. Our results propose a possible mechanism of CHST11 in regulating GBM malignancy and highlight a novel strategy for targeting aberrant chondroitin sulfate in GBM cells.

Targeting Chondroitin Sulphate Synthase 1 (Chsy1) Promotes Axon Growth Following Neurorrhaphy by Suppressing Versican Accumulation.

Versican is a chondroitin sulfate proteoglycan (CSPG), which deposits in perineurium as a physical barrier and prevents the growth of axons out of the fascial boundary. Several studies have indicated that the chondroitin sulfate (CS) chains on versican have several possible functions beyond the physical barrier, including the ability to stabilize versican core protein in the extracellular matrix. As chondroitin sulfate synthase 1 (Chsy1) is a crucial enzyme for CS elongation, we hypothesized that in vivo knockdown of Chsy1 at peripheral nerve lesion site may decrease CS and versican accumulation, and result in accelerating neurite regeneration. In the present study, end-to-side neurorrhaphy (ESN) in Wistar rats was used as an in vivo model of peripheral nerve injury to evaluate nerve regeneration after surgical intervention. The distribution and expression of versican and Chsy1 in regenerating axons after ESN was studied using confocal microscopy and western blotting. Chsy1 was silenced at the nerve lesion (surgical) site using in vivo siRNA transfection. The results indicated that Chsy1 was successfully silenced in nerve tissue, and its downregulation was associated with functional recovery of compound muscle action potential. Silencing of Chsy1 also decreased the accumulation of versican core protein, suggesting that transient treating of Chsy1-siRNA may be an alternative and an effective strategy to promote injured peripheral nerve regeneration.

Liraglutide Attenuates Glucolipotoxicity-Induced RSC96 Schwann Cells' Inflammation and Dysfunction.

Diabetic neuropathy (DN) is a type of sensory nerve damage that can occur in patients with diabetes. Although the understanding of pathophysiology is incomplete, DN is often associated with structural and functional alterations of the affected neurons. Among all possible causes of nerve damage, Schwann cells (SCs) are thought to play a key role in repairing peripheral nerve injury, suggesting that functional deficits occurring in SCs may potentially exhibit their pathogenic roles in DN. Therefore, elucidating the mechanisms that underlie this pathology can be used to develop novel therapeutic targets. In this regard, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently attracted great attention in ameliorating SCs' dysfunction. However, the detailed mechanisms remain uncertain. In the present study, we investigated how GLP-1 RA Liraglutide protects against RSC96 SCs dysfunction through a diabetic condition mimicked by high glucose and high free fatty acid (FFA). Our results showed that high glucose and high FFAs reduced the viability of RSC96 SCs by up to 51%, whereas Liraglutide reduced oxidative stress by upregulating antioxidant enzymes, and thus protected cells from apoptosis. Liraglutide also inhibited NFκB-mediated inflammation, inducing SCs to switch from pro-inflammatory cytokine production to anti-inflammatory cytokine production. Moreover, Liraglutide upregulated the production of neurotrophic factors and myelination-related proteins, and these protective effects appear to be synergistically linked to insulin signaling. Taken together, our findings demonstrate that Liraglutide ameliorates diabetes-related SC dysfunction through the above-mentioned mechanisms, and suggest that modulating GLP-1 signaling in SCs may be a promising strategy against DN.

Amitriptyline improves cognitive and neuronal function in a rat model that mimics dementia with lewy bodies.

Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and ß-amyloid (Aß). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 µg/10 µL) and Aß (5 µg/2.5 µL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.

Anti-apoptotic effects of diosgenin on ovariectomized hearts.

BACKGROUND: The anti-apoptotic effects of diosgenin, a steroid saponin, on hearts in female with estrogen deficiency have been less studied. This study aimed to evaluate the anti-apoptotic effects of diosgenin on cardiac widely dispersed apoptosis in a bilateral ovariectomized animal model. METHODS: A total of 60 female Wistar rats, aged 6-7 months, were divided into the sham-operated group (Sham), bilateral ovariectomized rats for 2 months, and ovariectomized rats administered with 0, 10, 50, or 100 mg/kg diosgenin daily (OVX, OVX 10, OVX 50, and OVX 100, respectively) in the second month. The excised hearts were analyzed by H&E staining, TUNEL(+) assays and Western Blot. RESULT: Cardiac TUNEL(+) apoptotic cells, the levels of Fas ligand, Fas death receptors, Fas-associated death domain, active caspase-8, and active caspase-3 (FasL/Fas-mediated pathways) as well as the levels of Bax, Bad, Bax/Bcl2, Bad/p-Bad, cytosolic Cytochrome c, active caspase-9, and active caspase-3 (mitochondria-initiated pathway) were increased in OVX compared with Sham group but those were decreased in OVX 50 compared with OVX. CONCLUSION: Diosgenin appeared to prevent or suppress ovariectomy-induced cardiac FasL/Fas-mediated and mitochondria-initiated apoptosis. These findings might provide one of the possible therapeutic approaches of diosgenin for potentially preventing cardiac apoptosis in women after bilateral ovariectomy or women with estrogen deficiency.

Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin ß1 Expression.

Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin ß1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin ß1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin ß1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma.

Neuroprotective Effects of Ceftriaxone Involve the Reduction of Aß Burden and Neuroinflammatory Response in a Mouse Model of Alzheimer's Disease.

Ceftriaxone (CEF) is a safe and multipotent antimicrobial agent that possesses neuroprotective properties. Earlier, we revealed the restoration of cognitive function in OXYS rats with signs of Alzheimer's disease (AD)-like pathology by CEF along with its modulating the expression of genes related to the system of amyloid beta (Aß) metabolism in the brain. The aim of this study was to determine the effects of CEF on behavior, Aß deposition, and associated neuroinflammation using another model of an early AD-like pathology induced by Aß. Mice were injected bilaterally i.c.v. with Aß fragment 25-35 to produce the AD model, while the CEF treatment (100 mg/kg/day, i.p., 36 days) started the next day after the surgery. The open field test, T-maze, Barnes test, IntelliCage, and passive avoidance test were used for behavioral phenotyping. Neuronal density, amyloid accumulation, and the expression of neuroinflammatory markers were measured in the frontal cortex and hippocampus. CEF exhibited beneficial effects on some cognitive features impaired by Aß neurotoxicity including complete restoration of the fear-induced memory and learning in the passive avoidance test and improved place learning in the IntelliCage. CEF significantly attenuated amyloid deposition and neuroinflammatory response. Thus, CEF could be positioned as a potent multipurpose drug as it simultaneously targets proteostasis network and neuroinflammation, as well as glutamate excitotoxicity, oxidative pathways, and neurotrophic function as reported earlier. Together with previous reports on the positive effects of CEF in AD models, the results confirm the potential of CEF as a promising treatment against cognitive decline from the early stages of AD progression.

Treatment with the combination of clavulanic acid and valproic acid led to recovery of neuronal and behavioral deficits in an epilepsy rat model.

Epilepsy, which is caused by abnormal neuronal firing in the brain, is a common neurological disease and affects motor and cognitive functions. Excessive levels of glutamate and insufficient levels of inhibitory GABA are involved in its pathophysiology. Valproic acid (Val), a GABAergic agonist, is one of the first-line antiepileptic drugs, but it shows many adverse side effects at the clinical dose. Clavulanic acid (CA), a ß-lactamase inhibitor, has been demonstrated to increase glutamate transporter-1 expression. This study evaluated the effects of CA and Val in an epilepsy rat model. Male Wistar rats received intraperitoneal injections of pentylenetetrazol (PTZ, 35 mg/kg, every other day, IP, for 13 days) to induce kindling epilepsy. After four times of PTZ injection, rats received daily treatment with CA (1 or 10 mg/kg, IP), Val (50 or 100 mg/kg, IP), or the combination of CA (1 mg/kg) and Val (50 mg/kg) for 7 consecutive days. Motor, learning, and memory functions were measured. Rats with PTZ-induced kindling exhibited seizures, motor dysfunction, cognitive impairment, and cell loss and reduction of neurogenesis in the hippocampus. Neither 1 mg/kg CA nor 50 mg/kg Val treatment was effective in alleviating behavioral and neuronal deficits. However, treatment with 10 mg/kg CA, 100 mg/kg Val, and the combination of 1 mg/kg CA and 50 mg/kg Val improved these behavioral and neuronal deficits. Particularly, the combination of CA and Val showed synergistic effects on seizure suppression, suggesting the potential for treating epilepsy and related neuronal damage and motor and cognitive deficits.

miR-302 Attenuates Mutant Huntingtin-Induced Cytotoxicity through Restoration of Autophagy and Insulin Sensitivity.

Huntington's disease (HD) is an autosomal-dominant brain disorder caused by mutant huntingtin (mHtt). Although the detailed mechanisms remain unclear, the mutational expansion of polyglutamine in mHtt is proposed to induce protein aggregates and neuronal toxicity. Previous studies have shown that the decreased insulin sensitivity is closely related to mHtt-associated impairments in HD patients. However, how mHtt interferes with insulin signaling in neurons is still unknown. In the present study, we used a HD cell model to demonstrate that the miR-302 cluster, an embryonic stem cell-specific polycistronic miRNA, is significantly downregulated in mHtt-Q74-overexpressing neuronal cells. On the contrary, restoration of miR-302 cluster was shown to attenuate mHtt-induced cytotoxicity by improving insulin sensitivity, leading to a reduction of mHtt aggregates through the enhancement of autophagy. In addition, miR-302 also promoted mitophagy and stimulated Sirt1/AMPK-PGC1α pathway thereby preserving mitochondrial function. Taken together, these results highlight the potential role of miR-302 cluster in neuronal cells, and provide a novel mechanism for mHtt-impaired insulin signaling in the pathogenesis of HD.

Treatment effects of the combination of ceftriaxone and valproic acid on neuronal and behavioural functions in a rat model of epilepsy.

NEW FINDINGS: What is the central question of this study? Imbalance of activities between GABAergic and glutamatergic systems is involved in epilepsy. It is not known whether simultaneously increasing GABAergic and decreasing glutamatergic activity using valproic acid and ceftriaxone, respectively, leads to better seizure control. What is the central question of this study? Ceftriaxone suppressed seizure and cognitive deficits and restored neuronal density and the number of newborn cells in the hippocampus in a rat model of epilepsy. Combined treatment with ceftriaxone and valproic acid showed additive effects in seizure suppression. ABSTRACT: The pathophysiology of epilepsy is typically considered as an imbalance between inhibitory GABA and excitatory glutamate neurotransmission. Valproic acid (Val), a GABA agonist, is one of the first-line antiepileptic drugs in the treatment of epilepsy, but it exhibits adverse effects. Ceftriaxone (CEF) elevates expression of glutamate transporter-1, enhances the reuptake of synaptic glutamate, increases the number of newborn cells and exhibits neuroprotective effects in animal studies. In this study, we evaluated effects of the combination of CEF and Val on behavioural and neuronal measures in a rat epilepsy model. Male Wistar rats were injected i.p. with pentylenetetrazol (35 mg/kg, every other day for 13 days) to induce the epilepsy model. Ceftriaxone (10 or 50 mg/kg), Val (50 or 100 mg/kg) or the combination of CEF and Val were injected daily after the fourth pentylenetetrazol injection for seven consecutive days. Epileptic rats exhibited seizure and impairments in motor and cognitive functions. Treatment with CEF and Val reduced the seizure and enhanced motor and cognitive functions in a dose-dependent manner. The combination of CEF (10 mg/kg) and Val (50 mg/kg) improved behaviours considerably. Histologically, compared with control animals, epileptic rats exhibited lower neuronal density and a reduction in hippocampal newborn cells but higher apoptosis in the basolateral amygdala, all of which were restored by the treatment with CEF, Val or the combination of CEF and Val. The study findings demonstrated that the combination of low doses of CEF and Val has beneficial effects on seizure suppression, neuroprotection and improvement in motor and cognitive functions in epilepsy.

CHPF Regulates the Aggressive Phenotypes of Hepatocellular Carcinoma Cells via the Modulation of the Decorin and TGF-ß Pathways.

Aberrant composition of glycans in the tumor microenvironment (TME) and abnormal expression of extracellular matrix proteins are hallmarks of hepatocellular carcinoma (HCC); however, the mechanisms responsible for establishing the TME remain unclear. We demonstrate that the chondroitin polymerizing factor (CHPF), an enzyme that mediates the elongation of chondroitin sulfate (CS), is a critical elicitor of the malignant characteristics of HCC as it modifies the potent tumor suppressor, decorin (DCN). CHPF expression is frequently downregulated in HCC tumors, which is associated with the poor overall survival of HCC patients. We observed that restoring CHPF expression suppressed HCC cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that TGF-ß signaling is associated with CHPF-induced phenotype changes. We found that DCN, as a TGF-ß regulator, is modified by CHPF, and that it affects the distribution of DCN on the surface of HCC cells. Importantly, our results confirm that CHPF and DCN expression levels are positively correlated in primary HCC tissues. Taken together, our results suggest that CHPF dysregulation contributes to the malignancy of HCC cells, and our study provides novel insights into the significance of CS, which affects DCN expression in the TME.

Syndecan-3 contributes to the regulation of the microenvironment at the node of Ranvier following end-to­side neurorrhaphy: sodium image analysis.

Syndecan-3 (SDC3) and Syndecan-4 (SDC4) are distributed throughout the nervous system (NS) and are favourable factors in motor neuron development. They are also essential for regulation of neurite outgrowth in the CNS. However, their roles in the reconstruction of the nodes of Ranvier after peripheral nerve injury (PNI) are still unclear. Present study used an in vivo model of end-to-side neurorrhaphy (ESN) for 1-3 months. The recovery of neuromuscular function was evaluated by grooming test. Expression and co-localization of SDC3, SDC4, and Nav1.6 channel (Nav1.6) at regenerating axons were detected by proximity ligation assay and confocal microscopy after ESN. Time-of-flight secondary ion mass spectrometry was used for imaging ions distribution on tissue. Our data showed that the re-clustering of sodium and Nav1.6 at nodal regions of the regenerating nerve corresponded to the distribution of SDC3 after ESN. Furthermore, the re-establishment of sodium and Nav1.6 correlated with the recovery of muscle power 3 months after ESN. This study suggested syndecans may involve in stabilizing Nav1.6 and further modulate the distribution of sodium at nodal regions after remyelination. The efficiency of sodium re-clustering was improved by the assistance of anionic syndecan, resulting in a better functional repair of PNI.

The Pluripotency Factor Nanog Protects against Neuronal Amyloid ß-Induced Toxicity and Oxidative Stress through Insulin Sensitivity Restoration.

Amyloid ß (Aß) is a peptide fragment of the amyloid precursor protein that triggers the progression of Alzheimer's Disease (AD). It is believed that Aß contributes to neurodegeneration in several ways, including mitochondria dysfunction, oxidative stress and brain insulin resistance. Therefore, protecting neurons from Aß-induced neurotoxicity is an effective strategy for attenuating AD pathogenesis. Recently, applications of stem cell-based therapies have demonstrated the ability to reduce the progression and outcome of neurodegenerative diseases. Particularly, Nanog is recognized as a stem cell-related pluripotency factor that enhances self-renewing capacities and helps reduce the senescent phenotypes of aged neuronal cells. However, whether the upregulation of Nanog can be an effective approach to alleviate Aß-induced neurotoxicity and senescence is not yet understood. In the present study, we transiently overexpressed Nanog-both in vitro and in vivo-and investigated the protective effects and underlying mechanisms against Aß. We found that overexpression of Nanog is responsible for attenuating Aß-triggered neuronal insulin resistance, which restores cell survival through reducing intracellular mitochondrial superoxide accumulation and cellular senescence. In addition, upregulation of Nanog expression appears to increase secretion of neurotrophic factors through activation of the Nrf2 antioxidant defense pathway. Furthermore, improvement of memory and learning were also observed in rat model of Aß neurotoxicity mediated by upregulation of Nanog in the brain. Taken together, our study suggests a potential role for Nanog in attenuating the neurotoxic effects of Aß, which in turn, suggests that strategies to enhance Nanog expression may be used as a novel intervention for reducing Aß neurotoxicity in the AD brain.

Anti-Apoptotic Effects of Diosgenin in D-Galactose-Induced Aging Brain.

The purpose of this study was to evaluate the effects of diosgenin on the D-galactose-induced cerebral cortical widely dispersed apoptosis. Male 12-week-old Wistar rats were divided into four groups: Control (1mg/kg/day of saline, i.p.), DD0 (150mg/kg/day of D-galactose, i.p.), DD10, and DD50 (D-galactose+10 or 50mg/kg/day of diosgenin orally). After eight weeks, histopathological analysis, positive TUNEL and Western blotting assays were performed on the excised cerebral cortex from all four groups. The TUNEL-positive apoptotic cells, the components of Fas pathway (Fas, FADD, active caspase-8 and active caspase-3), and mitochondria pathway (t-Bid, Bax, cytochrome c, active caspase-9 and active caspase-3) were increased in the DD0 group compared with the control group, whereas they were decreased in the DD50 group. The components of survival pathway (p-Bad, Bcl-2, Bcl-xL, IGF-1, p-PI3K and p-AKT) were increased in the DD50 group compared to the control group, whereas the levels of Bcl-xL, p-PI3K, and p-AKT were also compensatorily increased in the DD0 group compared to the control group. Taken together, diosgenin suppressed D-galactose-induced neuronal Fas-dependent and mitochondria-dependent apoptotic pathways and enhanced the Bcl-2 family associated pro-survival and IGF-1-PI3K-AKT survival pathways, which might provide neuroprotective effects of diosgenin for prevention of the D-galactose-induced aging brain.

Chondroitin sulfate synthase 1 enhances proliferation of glioblastoma by modulating PDGFRA stability.

Chondroitin sulfate synthases, a family of enzyme involved in chondroitin sulfate (CS) polymerization, are dysregulated in various human malignancies, but their roles in glioma remain unclear. We performed database analysis and immunohistochemistry on human glioma tissue, to demonstrate that the expression of CHSY1 was frequently upregulated in glioma, and that it was associated with adverse clinicopathologic features, including high tumor grade and poor survival. Using a chondroitin sulfate-specific antibody, we showed that the expression of CHSY1 was significantly associated with CS formation in glioma tissue and cells. In addition, overexpression of CHSY1 in glioma cells enhanced cell viability and orthotopic tumor growth, whereas CHSY1 silencing suppressed malignant growth. Mechanistic investigations revealed that CHSY1 selectively regulates PDGFRA activation and PDGF-induced signaling in glioma cells by stabilizing PDGFRA protein levels. Inhibiting PDGFR activity with crenolanib decreased CHSY1-induced malignant characteristics of GL261 cells and prolonged survival in an orthotopic mouse model of glioma, which underlines the critical role of PDGFRA in mediating the effects of CHSY1. Taken together, these results provide information on CHSY1 expression and its role in glioma progression, and highlight novel insights into the significance of CHSY1 in PDGFRA signaling. Thus, our findings point to new molecular targets for glioma treatment.

Melatonin Promotes Nerve Regeneration Following End-to-Side Neurorrhaphy by Accelerating Cytoskeletal Remodeling via the Melatonin Receptor-dependent Pathway.

Acceleration of cytoskeletal remodeling in regenerated axons is crucial for a fully functional recovery following peripheral nerve injury (PNI). Melatonin plays important roles in cell differentiation and protection of cytoskeleton stability, thus, the present study aimed to investigate whether melatonin can enhance neurite outgrowth and promote cytoskeletal remodeling in a PNI animal model and in differentiated neurons. End-to-side neurorrhaphy (ESN) rat model was used for assessing cytoskeletal rearrangement in regenerated axon. Subject rats received 1 mg/kg/day melatonin injection for one month. The amplitude of compound muscle action potentials and the number of re-innervated motor end plates on target muscles were assessed to represent the functional recovery after ESN. Melatonin treatment enhanced functional recovery after ESN, compared to the saline treated group. Additionally, in spinal cord and peripheral nerve tissue, animals receiving melatonin displayed enhanced expression of GAP43 and ß3-tubulin one month after ESN, and an increased number of re-innervated motor end plates on their target muscle. In vitro analysis revealed that melatonin treatment significantly promoted neurite outgrowth, and increased expression of melatonin receptors as well as ß3-tubulin in mouse neuroblastoma Neuro-2a (N2a) cells. Treatment with a melatonin receptor antagonist, luzindole, significantly suppressed melatonin receptors and ß3-tubulin expression. Importantly, we found that melatonin treatment suppressed activation of calmodulin-dependent protein kinase II (CaMKII) in vitro and in vivo, suggesting that the ß3-tubulin remodeling may occur via CaMKII-mediated Ca2+ signaling. These results suggested that melatonin may promote functional recovery after PNI by accelerating cytoskeletal remodeling through the melatonin receptor-dependent pathway.

Use of Ceftriaxone in Treating Cognitive and Neuronal Deficits Associated With Dementia With Lewy Bodies.

Dementia with Lewy bodies (DLB) is caused by accumulation of Lewy bodies, destruction of mitochondria, and excess of glutamate in synapses, which eventually leads to excitotoxicity, neurodegeneration, and cognitive impairments. Ceftriaxone (CEF) reduces excitotoxicity by increasing glutamate transporter 1 expression and glutamate reuptake. We investigated whether CEF can prevent cognitive decline and neurological deficits and increase neurogenesis in DLB rats. Male Wistar rats infused with viral vector containing human alpha-synuclein (α-syn) gene, SNCA, in the lateral ventricle were used as a rat model of DLB. CEF (100 mg/kg/day, i.p.) was injected in these rats for 27 days. The active avoidance test and object recognition test was performed. Finally, the brains of all the rats were immunohistochemically stained to measure α-syn, neuronal density, and newborn cells in the hippocampus and substantia nigra. The results revealed that DLB rats had learning and object recognition impairments and exhibited cell loss in the nigrostriatal dopaminergic system, and hippocampal CA1, and dentate gyrus (DG). Additionally, DLB rats had fewer newborn cells in the DG and substantia nigra pars reticulata and more α-syn immune-positive cells in the DG. Treatment with CEF improved cognitive function, reduced cell loss, and increased the number of newborn cells in the brain. To our knowledge, this is the first study showing that CEF prevents loss of neurogenesis in the brain of DLB rats. CEF may therefore has clinical potential for treating DLB.

Using a numerical method to precisely evaluate the alpha angle in a hip image.

The alpha angle is a parameter extensively used to assess for cam-type femoroacetabular impingement (FAI) in a 2D image of the hip. As this angle requires estimation of the axis of the femoral neck, the drawing of this axis often results in measurement errors due to subjective judgment, influencing inter-rater and intra-rater agreements. In the present study, sampling points were captured from the edges of a femoral neck and head in the 2D image, and the best curves of the two were fitted respectively by using the curve fitting method. The morphology of the femoral neck was outlined by two polynomials, and the femoral head was represented by an equation of a circle. By means of the proposed method, the results reveal that the inter-rater ICCs in X-ray and MRI were respectively 0.905 and 0.969, and the intra-rater ICCs in X-ray and MRI were respectively 0.892 and 0.840. The Bland-Altman plot shows that the values obtained by the proposed method and the conventional method were not consistent; nevertheless, the linear regression analysis indicated the two measurement results had a significant association (p < 0.001). This study provides a repeatable and agreed α angle measuring method, which contributes to identifying normal and abnormal femoral head-neck morphologies. The proposed numerical method would contribute to diagnose early FAI.

A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects.

Several neurodegenerative disorders, namely Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and ß-amyloid (Aß). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aß metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF.