Depression and anxiety disorders in patients with multiple sclerosis: association with neurodegeneration and neurofilaments

There is increasing evidence that neurofilament light chain (NF-L) can be considered as a biomarker for neuro-axonal damage. This polypeptide can be released into the cerebrospinal fluid (CSF) and the blood, where it can be quantified. The concentration of NF-L is elevated in patients with multiple sclerosis (MS) and psychiatric disorders. We aimed to investigate the NF-L levels in the CSF from treated MS patients and the relationship with depression or anxiety. The study involved three groups: control group (individuals without inflammation), the relapse-remitting multiple sclerosis (RRMS)-untreated group, and the RRMS-Fingo group (RRMS patients who were treated with fingolimod). MS disability was assessed by the Expanded Disability Status Scale, and depression and anxiety were evaluated by a neuropsychologist, using the Hospital Anxiety and Depression Scale, the Beck Depression Inventory-II, and the Beck Anxiety Inventory. Individual CSF samples were collected to measure NF-L levels. The results of the statistical analysis on levels of NF-L in the CSF of control subjects, RRMS-untreated patients, and RRMS-Fingo patients were significant. The relationship between depression and anxiety in RRMS-Fingo patients and NF-L levels was not statistically significant. In conclusion, MS events such as anxiety and depression appear to contribute to the onset of clinical relapses, subclinical cases, and neurodegeneration.

Factores pronósticos de la Esclerosis Múltiple / Prognostic factors in Multiple Sclerosis

Resumen La Esclerosis Múltiple es una enfermedad inflamatoria y degenerativa del Sistema Nervioso Central que afecta a la población adulta joven. La prevalencia de esta entidad es heterogénea en el mundo y baja en el Ecuador. El diagnóstico se basa en los criterios de McDonald 2017. Una vez que el diagnóstico se ha establecido, es necesario determinar si los pacientes tienen factores de mal pronóstico los cuales van a generar un impacto en el tipo de tratamiento a elegir. Al momento, se han estudiado factores pronósticos epidemiológicos, clínicos, biomoleculares y de imagen los cuales nos permiten predecir si la enfermedad tiene un comportamiento agresivo o por el contrario un curso benigno. El número de lesiones en las imágenes de resonancia magnética cerebral, la presencia de lesiones en tronco encefálico y médula espinal son los factores que han demostrado tener un impacto en la progresión de discapacidad. La presencia de bandas oligoclonales en el líquido cefalorraquídeo tiene un rol fundamental en la conversión de un síndrome clínico aislado en esclerosis múltiple clínicamente establecida. Los niveles bajos de vitamina D ha demostrado estar asociado con mal pronóstico pero su aplicabilidad en países como el Ecuador es aún tema de investigación.

Abstract Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system which affects young adults. The prevalence of multiple sclerosis in the world is heterogeneous and is low in Ecuador. The diagnosis is based on the McDonald 2017 criteria. Once the diagnosis has been made, it is necessary that any negative factors which will impact the type of treatment used be identified. At this time, factors such as epidemiological, clinical, biomolecular, and magnetic resonance images, which will allow us to identify if the case is aggressive or benign, are studied. The number of lesions shown in a brain MRI, the presence of lesions in the brain stem and spinal cord are factors which have been demonstrated to have an impact on the progression of disability. The presence of oligoclonal bands in the cerebrospinal fluid has a fundamental role in the conversion of an isolated clinical syndrome to multiple sclerosis. Low levels of vitamin D have been associated with a negative prognosis, however how important vitamin D is in the prognosis of MS in countries such as Ecuador is still an area to be studied.

The protective effects of dipeptidyl peptidase-4 inhibitor on AD-like neurodegenerative changes / 天津医药

Objective To explore the protective effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) on AD-like neurodegenerative changes and its mechanism. Methods The human neuroblastoma cell line SH-SY5Y on the logarithmic phase was divided into six groups:control group (CON group, treated with PBS contained 1‰DMSO for 12 h), wortmannin intervention group (W group, treated with 0.03 μmol/L wortmannin for 12 h), DPP-4I intervention group (DPP-4I group, treated with 10μmol/L DPP-4I for 12 h), both DPP-4I and wortmannin intervention group (DPP-4I+W group, pre-treated with 10 μmol/L DPP-4I for 2 h, then 0.03 μmol/L wortmannin for 12 h), DPP-4I, wortmannin and Ex9-39 intervention group (DPP-4I+W+Ex9-39 group, pre-treated with 10μmol/L Ex9-39 for 2 h, then 10μmol/L DPP-4I for 2 h followed by 0.03μmol/L wortmannin for 12 h), and Ex9-39 intervention group (Ex9-39 group, treated with 10μmol/L Ex9-39 for 12 h). MTT assay was used to detect the cell vitality. Western blot assay was used to detect the level of total tau protein (tau-5) and phosphorylated tau at different sites (pSpS199/202, pT231 and pS396), the level of phosphorylated neurofilaments (NF-H, NF-M) and phosphorylation of critical enzyme in PI3K/Akt/GSK-3β signaling pathway. Results (1) The cell vitality decreased, the levels of pSpS199/202, pT231, pS396 and NF-H/M increased significantly in W group than those in CON group. However, comparing with CON group, the above mentioned parameters reversed in DPP-4I group. Comparing with W group, the cell vitality increased and phosphorylated levels of above mentioned indices were decreased in DPP-4I+W group. (2) The cell vitality showed a decline trend while the levels of phosphorylation tau at three different sites and NF-H/M were higher in Ex9-39 group than those in CON group. Comparing with DPP-4I+W group, the results of the phosphorylated levels showed the same changes in DPP-4I+W+Ex9-39 group. (3) Comparing with CON group, the expression levels of phosphorylated PI3K, Akt and GSK3β increased significantly in DPP-4I group, while those decreased in W group. Additionally, the expression levels of phosphorylated PI3K, Akt and GSK3β were significantly increased in DPP-4I+W group than those in W group. Conclusion DPP-4I can enhance the level of GLP-1 and activate PI3K/Akt/GSK-3βinsulin signaling pathway to improve the hyperphosphorylated tau and NFs induced by wortmannin, and to protect AD-like neurodegeneration.

The effects of liraglutide on learning and memory in Alzheimer-like triple transgenic mice with type 2 diabetes / 天津医药

Objective To investigate the effects of type 2 diabetes on learning and memory of APP/PS1/Tau triple transgenic (3 × Tg) mice of Alzheimer’s disease, and the protective mechanism of liraglutide (LIR) thereof. Methods One month old C57BL/6 mice were set to be control group (WT). One month old 3×Tg mice were divided into control group (Tg), liraglutide group (Tg+LIR), type 2 diabetes group (Tg+T2DM) and liraglutide treatment group (Tg+T2DM+LIR). The model of T2DM was established by feeding the high fat and sugar fodder, and then injecting streptozotocin (STZ) in mice, making sure the fasting blood glucose was more than 7 mmol/L. Then the subcutaneous injection of LIR was administered for 2 months. The values of body weight and fasting blood glucose were detected at age of 5-month. Morris water maze was applied to evaluate the spatial learning and memory ability. Western blotting assay was used to measure the levels of phosphorylated Tau, neurofilament (NFs) and insulin receptor substrates. ELISA was used to detect the human Aβ42 to evaluate the effect of LIR on-amyloid. Results LIR can reduce body weight and blood glucose, can alleviate spatial learning and memory damaging caused by T2DM, and also can improve phosphorylated Tau levels, NFs and insulin receptor substrates caused by T2DM, and finally can reduce the deposition ofβ-amyloid of 3 × Tg mice. Conclusion T2DM can aggravate symptoms of AD in 3×Tg mice, and LIR has a protective effect on it.

Analisis comparativo del número de neurofilamentos en nervios isquiáticos de rata sometidos a neuropraxia tratadas con láser de baja intensidad y ultrasonido terapéutico / Comparative analysis of the number of neurofilaments in rat sciatic nerve undergoing neuropraxia treated by low-level laser and therapeutic ultrasound

Es habitual que tras una compresión nerviosa se aplique terapia, ya sea, a través de laser de baja intensidad (LBI) o ultrasonido (US). El objetivo de este trabajo fue determinar la efectividad de dichos tratamientos para reparar el citoesqueleto neuronal evaluando la variación en el número de neurofilamentos. Se realizó un diseño experimental, en el cual se utilizaron 30 ratas que fueron separadas en 6 grupos: 1- control sano; 2- control lesionado; 3- irradiado con LBI 2J/cm2; 4- irradiado con LBI 10 J/cm2; 5- irradiado con US 0,5W/cm2 y 6- irradiado con US 1W/cm2. Con excepción del grupo 1 los especímenes fueron anestesiados y se les realizó la compresión del nervio isquiático derecho utilizando una presión de 40N durante 45 segundos. Veinticuatro horas después de la compresión se inició la irradiación con LBI y US, según protocolo. En nuestra investigación constatamos que el incremento en el número de neurofilamentos se relacionó con la dosis aplicada de LBI y US. El valor medio de neurofilamentos/0,25 mm2 obtenidos en cada grupo fue: 1 - 128; 2 - 100; 3 - 156; 4 - 140; 5 - 100; 6 - 148. La aplicación de LBI de y de US terapéutico aumenta el número de neurofilamentos en nervios isquiáticos de rata sometidos a neuropraxia, siendo el LBI más eficaz en comparación al US. Se agrega que estas terapias para inducir la regeneración del nervio lesionado se relacionan al tipo de protocolo utilizado, lo que demuestra la necesidad de establecer la adecuada dosis de irradiación con el propósito de obtener la mejor respuesta terapéutica.

Therapy by low-level laser (LLL) or ultrasound (US) are commonly used as treatment after nerve crush. The aim of this study was to determine the effectiveness of such treatments to repair the neuronal cytoskeleton evaluating the variation in the number of neurofilaments. For this an experimental design was performed, which involved 30 rats divided into 6 groups: 1 - control healthy; 2 - control injured; 3 - irradiated by LLL 2 J/cm2; 4 - irradiated by LLL 10 J/cm2; 5 - irradiated by US 0.5 W/cm2 and 6 - irradiated by US 1W/cm2. With the exception of group 1 all specimens were anesthetized and underwent right sciatic nerve compression using 40N pressure for 45 seconds. Twenty-four hours after compression irradiation was started by LLL and US according protocol. In our research we found that the increase in the number of neurofilaments was related to the applied dose of LLL and US. The average value of neurofilaments / 0.25 mm2 obtained in each group was: 1 - 128; 2-100; 3-156; 4-140; 5-100; 6-148. We concluded that the application of LLL and therapeutic US increases the number of neurofilaments in rat sciatic nerve undergoing neuropraxia, with LLL being more effective compared to the US. Furthermore we concluded that the effectiveness of therapies to induce regeneration of injured nerve is related to the type of protocol used, demonstrating the need to establish an adequate radiation dose with the purpose of obtaining the best therapeutic response, thus achieving successful treatment.

Effects of transplanting bone marrow stromal cells on axonal and glial scarring after spinal cord injury / 中华物理医学与康复杂志

Objective To investigate the effects of bone marrow stromal cell (BMSC) transplantation on axonal and glial scarring after spinal cord injury (SCI).Methods Thirty New Zealand white rabbits were randomly assigned to a sham operation group (group A),a saline treatment group (group B) or a BMSC treatment group (group C).Group A served as controls,in which the canal was opened without damage to the spinal cord.In groups C and B SCI models were established with aneurysm clips and the rabbits of groups C and B were then given injections of BMSCs and saline solution respectively via the intra-intercostal artery at 1 week post injury.At 1 day,1 week,2 weeks and 4 weeks post injury,Basso Beattie-Bresnahan (BBB) scores were assessed to evaluate the recovery of locomotor function in the hind limbs.Spinal cord samples were harvested for HE and Nissl staining,and immunohistochemistry and image analysis were used to detect any changes in neurofilament (NF200) and glial fibrillary acidic protein (GFAP) in the injured spinal cords.Results The average BBB scores of group A were significantly higher those that of groups B and C at each time point,and those of group C were significantly better than those of group B at the 2nd and 4th week post injury.At the 4th week post injury,HE staining showed there was no glial scarring or cavities in group A,but that there was glial cellular proliferation,glial scarring and cavity formation at the injury site in groups B and C.In group C all were obviously less than in group B.Nissl staining indicated there were more typical neurons in group A,while there were a larger number of ruptured neurons,more degradation,and irregular remaining neurons in groups B and C.These abnormalities were again significantly more prevalent in group C.Immunohistochemical examination showed significant increases in NF200 positive neurons and GFAP in groups B and C compared with group A.The number of NF200 positive neurons was significantly higher in group C than in group B,but the GFAP positive area was significantly smaller in group C than in group B.Conclusion BMSC transplantation via the intercostal arteries can effectively improve axonal regeneration,attenuate glial cellular proliferation and reduce glial scar formation,promoting functional recovery after SCI,at least in rabbits.