Degenerative Changes In Neurons Research Articles

BDNF/TrkB activators in Parkinson's disease: A new therapeutic strategy.

Parkinson's disease (PD) is a neurodegenerative disorder of the brain and is manifested by motor and non-motor symptoms because of degenerative changes in dopaminergic neurons of the substantia nigra. PD neuropathology is associated with mitochondrial dysfunction, oxidative damage and apoptosis. Thus, the modulation of mitochondrial dysfunction, oxidative damage and apoptosis by growth factors could be a novel boulevard in the management of PD. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase type B (TrkB) are chiefly involved in PD neuropathology. BDNF promotes the survival of dopaminergic neurons in the substantia nigra and enhances the functional activity of striatal neurons. Deficiency of the TrkB receptor triggers degeneration of dopaminergic neurons and accumulation of α-Syn in the substantia nigra. As well, BDNF/TrkB signalling is reduced in the early phase of PD neuropathology. Targeting of BDNF/TrkB signalling by specific activators may attenuate PD neuropathology. Thus, this review aimed to discuss the potential role of BDNF/TrkB activators against PD. In conclusion, BDNF/TrkB signalling is decreased in PD and linked with disease severity and long-term complications. Activation of BDNF/TrkB by specific activators may attenuate PD neuropathology.

Lyssavirus M protein degrades neuronal microtubules by reprogramming mitochondrial metabolism.

Infection with neurotropic viruses may result in changes in host behavior, which are closely associated with degenerative changes in neurons. The lyssavirus genus comprises highly neurotropic viruses, including the rabies virus (RABV), which has been shown to induce degenerative changes in neurons, marked by the self-destruction of axons. The underlying mechanism by which the RABV degrades neuronal cytoskeletal proteins remains incomplete. In this study, we show that infection with RABV or overexpression of its M protein can disrupt mitochondrial metabolism by binding to Slc25a4. This leads to a reduction in NAD+ production and a subsequent influx of Ca2+ from the endoplasmic reticulum and mitochondria into the cytoplasm of neuronal cell lines, activating Ca2+-dependent proteinase calpains that degrade α-tubulin. We further screened the M proteins of different lyssaviruses and discovered that the M protein of the dog-derived RABV strain (DRV) does not degrade α-tubulin. Sequence analysis of the DRV M protein and that of the lab-attenuated RABV strain CVS revealed that the 57th amino acid is vital for M-induced microtubule degradation. We generated a recombinant RABV with a mutation at the 57th amino acid position in its M protein and showed that this mutation reduces α-tubulin degradation in vitro and axonal degeneration in vivo. This study elucidates the mechanism by which lyssavirus induces neuron degeneration.IMPORTANCEPrevious studies have suggested that RABV (rabies virus, the representative of lyssavirus) infection induces structural abnormalities in neurons. But there are few articles on the mechanism of lyssavirus' effect on neurons, and the mechanism of how RABV infection induces neurological dysfunction remains incomplete. The M protein of lyssavirus can downregulate cellular ATP levels by interacting with Slc25a4, and this decrease in ATP leads to a decrease in the level of NAD+ in the cytosol, which results in the release of Ca2+ from the intracellular calcium pool, the endoplasmic reticulum, and mitochondria. The presence of large amounts of Ca2+ in the cytoplasm activates Ca2+-dependent proteases and degrades microtubule proteins. The amino acid 57 of M protein is the key site determining its disruption of mitochondrial metabolism and subsequent neuron degeneration.

Ultrastructural changes in the rat retina in the presence of long-term opioid exposure

Purpose: To determine the features of the untrastructural reorganization in the rat retina by the end of week 4 and week 6 of experimental opioid exposure. Material and Methods: Forty-eight adult male albino rats (weight, 200-250 g; age, 4.5 months) were used in this study. They received nalbuphine hydrochloride intramuscularly daily for 42 days. Particularly, the drug was administered daily at a dose of 0.212 mg/kg for weeks 1 and 2, 0.225 mg/kg for weeks 3 and 4, and 0.252 mg/kg for weeks 5 and 6. In this way, we experimentally created the conditions of chronic opioid exposure. Animals were divided into three groups. Group 1 (19 animals) received nalbuphine for 28 days, and group 2 (19 animals), for 42 days. Group 3 (control group) comprised 10 animals. Of these, 5 animals were treated with normal saline at a dose of 0.22 mg/kg intramuscularly daily for 28 days, and the rest were treated in a similar manner for 42 days. Transmission electron microscopy studies of the rat retina were conducted in a routine manner. Results: By the end of week 4 of experimental opioid exposure, there was an increase in the number of retinal microvessels with signs of hyperemia and degenerative changes in retinal pigment epithelium (RPE) cells, increase in the destruction of membranous discs of photoreceptor outer segments, necrobiotic changes in the nuclei of individual photoreceptors, axonal degeneration in the outer and inner plexiform layers, degenerative changes in retinal horizontal neurons, and the appearance of necrotic structural changes in the cytoplasm of bipolar and amacrine cells. By the end of week 6, there was a further increase in hyperemia of retinal vessels and degenerative and necrotic changes in individual RPE cells and photoreceptor outer segments. In addition, we observed destruction and shortening of mitochondrial cristae of photoreceptor inner segments, necrotic nuclear changes in individual photoreceptors, degeneration of axons of the outer and inner plexiform layers, degenerative and necrotic changes in bipolar and amacrine cells, hypertrophic Müller cell processes, degeneration of ganglion cells, and vascular hyperemia and moderate perivascular edema in the outer and inner plexiform layers. Conclusion: Therefore, in the current rat study, after a 4-week exposure to daily nalbuphine injections at a dose ranging 0.212 to 0.253 mg/kg, there was ultrastuctural evidence of destructive processes in the RPE and photoreceptor outer segments, axonal degeneration in the outer and inner plexiform layers, degenerative and necrotic changes in bipolar and amacrine cells, hypertrophic Müller cell processes, ganglion cell degeneration and hyperemia due to an impaired retinal microcirculatory ultrastructure. At week 6 of the experiment, there was evidence of increased destructive and degenerative processes in structural components of the retina.

Behavioral, neural and ultrastructural alterations in a graded-dose 6-OHDA mouse model of early-stage Parkinson's disease

Studying animal models furthers our understanding of Parkinson’s disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson’s disease in mice.

TNF-α blockage by etanercept restores spatial learning and reduces cellular degeneration in the hippocampus during liver cirrhosis

Hepatic encephalopathy (HE) is one of the most debilitating cerebral complications of liver cirrhosis. The one-year survival of patients with liver cirrhosis and severe encephalopathy is less than 50%. Recent studies have indicated that neuroinflammation is a new player in the pathogenesis of HE, which seems to be involved in the development of cognitive impairment. In this study, we demonstrated neurobehavioral and neuropathological consequences of liver cirrhosis and tested the therapeutic potential of the tumor necrosis factor-α (TNF-α) inhibitor, etanercept. Sixty male adult Wistar albino rats (120–190 g) were allocated into four groups, where groups I and IV served as controls. Thioacetamide (TAA; 300 mg/kg) was intraperitoneally injected twice a week for five months to induce liver cirrhosis in group II (n = 20). Both TAA and etanercept (2 mg/kg) were administered to group III (n = 20). At the end of the experiment, spatial learning was assessed using Morris water maze. TNF-α was detected in both serum and hippocampus. The excised brains were also immunohistochemically stained with glial fibrillary acidic protein (GFAP) to estimate both the number and integrity of hippocampal astrocytes. Ultrastructural changes in the hippocampus were characterized by transmission electron microscopy. The results showed that blocking TNF-α by etanercept was accompanied by a lower TNF-α expression and a higher number of GFAP-positive astrocytes in the hippocampus. Etanercept intervention alleviated the neuronal and glial degenerative changes and impeded the deterioration of spatial learning ability. In conclusion, TNF-α is strongly involved in the development of liver cirrhosis and the associated encephalopathy. TNF-α blockers may be a promising approach for management of hepatic cirrhosis and its cerebral complications.

Electro-physiological Changes in the Central Nervous System by Visual Evoked Potential in Diabetic Patients.

Increasing sedentary lifestyle in today's world has increased the prevalence of Diabetes Mellitus. Loss of vision due to diabetic retinopathy is a major public health burden. Visual evoked potential identifies the neuronal degenerative changes in chronic metabolic disorders specially Diabetes Mellitus. The study aimed at evaluating changes in visual evoked potential waves in diabetic patients. This is a cross sectional comparative study consisting of 90 participants, out of which 60 were diabetic patients and 30 were non-diabetic control group. Among diabetic patients, 30 were without retinopathy, 10 with mild non-proliferative retinopathy, 10 with moderate non-proliferative retinopathy and 10 with severe non-proliferative retinopathy. Visually evoked potential latencies and amplitudes were compared among diabetic patients and the control group and also among individuals with different grades of retinopathy. Delay in P100 latency and decrease in its amplitude were statistically significant in diabetic patients. The changes in P100 latency, P100 amplitude and N75 latency were also significant in different grades of retinopathy. There are statistically significant changes in visually evoked potential in diabetes patients. Visual evoked potential is a useful, non-invasive investigation which can establish the central nervous system neuropathy in diabetes at an early stage of the disease. So Diabetic retinopathy can be prevented due to early detection of neuropathy by visual evoked potential test Keywords: Diabetes mellitus; diabetic retinopathy; visual evoked potential.

Naringenin stimulates aromatase expression and alleviates the clinical and histopathological findings of experimental autoimmune encephalomyelitis in C57bl6 mice.

This study was conducted to demonstrate the possible protective and therapeutic effects of naringenin, an estrogenically effective flavonoid, in experimental autoimmune encephalomyelitis (EAE), which is the rodent model of multiple sclerosis. For this purpose, 50 12-week-old C57BL6 male mice were divided into five groups; control, naringenin, EAE, prophylactic naringenin + EAE, and EAE + therapeutic naringenin. The EAE model was induced withmyelin oligodendrocyte glycoprotein(35-55), and naringenin (50mg/kg) was administered by oral gavage. The prophylactic and therapeutic effects of naringenin were examined according to clinical, histopathological, immunohistochemical, electron microscopic, and RT-PCR (aromatase, 3βHSD, estrogen receptors, and progesterone receptor expression) parameters. The acute EAE model was successfully induced, along with its clinical and histopathological findings. RT-PCR showed that expression of aromatase, 3βHSD, estrogen receptor-β, and progesterone receptor gene decreased, while estrogen receptor-α increased after EAE induction. Electron microscopic analysis showed mitochondrial damage and degenerative changes in myelinated axons and neurons in EAE, which could be behind the downregulation in the expressions of neurosteroid enzymes. Aromatase immunopositivity rates also decreased in EAE, while estrogen receptor α and β, and progesterone receptor immunopositivity rates increased. Naringenin improved aromatase immunopositivity rates and gene expression in both prophylactic and therapeutic use. Clinical and histopathological findings revealed that EAE findings were alleviated in both prophylactic and therapeutic groups, along with significantly decreased inflammatory cell infiltrations in the white matter of the spinal cords. In conclusion, naringenin could provide long-term beneficial effects even in prophylactic use due to stimulating aromatase expression, but it could not prevent or eliminate the EAE model's lesions completely.

Оценка периоперационного статуса детей с СМА на фоне терапии нусинерсеном при реконструктивных ортопедических вмешательствах

Surgical methods for treatment of spinal muscular atrophy (SMA) in children are aimed at improving their positioning and maintaining the ability of verticalization. Assessment of neurological, somatic and motor status of patients, individual selection of drugs for anesthesia and sedation at the stage of planning surgical interventions allow the anesthesiologist/resuscitator to avoid perioperative adverse events. Purpose To compare the course of the perioperative period in children with SMA who received pathogenetic therapy with nusinersen with the control group during orthopedic correction of acquired skeletal deformities. Materials and methods The retrospective analysis for the period from 2019 to 2021 included 23 children. Depending on the ongoing pathogenetic therapy, children with SMA were divided into 2 groups. The main group (SMA+N) included 9 children who received nusinersen; the control group (CG) included 14 children without antisense oligonucleotide therapy. Co-morbidities, hemodynamic parameters, blood loss, need for analgesics and complications were studied. Results Insignificant differences between the groups were recorded based on the Hammersmith Extended Scale (HFMSE). At the same time, similar comorbid pathology, the severity of respiratory failure, and the absence of differences in the frequency of the NIV application indicated that the groups were comparable. This is probably due to the late start of SMA treatment, degenerative changes in motor neurons, and fatty degeneration of muscle tissue. Conclusion Intake of nusinersen in patients with SMA type II-III and a long period of illness, severe neurological and respiratory disorders do not lead to a significant regression of symptoms in the perioperative period. The therapy with antisense oligonucleotides in severe muscle hypotonia does not exclude the risk of adverse events in the perioperative period in children with SMA type II-III during orthopedic correction of skeletal deformities.

Probiotic Formulation VSL#3 Interacts with Mesenchymal Stromal Cells To Protect Dopaminergic Neurons via Centrally and Peripherally Suppressing NOD-Like Receptor Protein 3 Inflammasome-Mediated Inflammation in Parkinson's Disease Mice.

Systemic immunomodulation is increasingly recognized among the beneficial effects of mesenchymal stromal cells (MSCs) in treatment of Parkinson's disease (PD), while the underlying mechanism is not fully understood. With the growing popularity of using probiotics as an adjuvant approach in PD treatment, concerns about the added effects of probiotics have been raised. In addition to the molecular mechanism mediating the neuroprotective effects of MSCs, the combined effects of a probiotic formulation, VSL#3, and MSC infusion were also evaluated in PD mice. The animals were weekly treated with human MSCs (hMSCs) via the tail vein, VSL#3 via the gastrointestinal tract, or their combination six times. hMSCs, VSL#3 alone, and their combination markedly ameliorated the decreased striatal dopamine content, loss of dopaminergic neurons in the substantia nigra, increased levels of proinflammatory cytokines in serum, as well as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) mRNAs in striatum and peripheral tissues induced by MPTP. Furthermore, hMSCs, VSL#3, and their combination notably downregulated mRNA expression of NOD-like receptor protein 3 (NLRP3) and caspase-1 in brain and peripheral tissues of PD mice. These results suggest that hMSCs, VSL#3, and their combination prevent neurodegenerative changes in PD mice via anti-inflammatory activities in both the central and peripheral systems, possibly through suppressing the NLRP3 inflammasome. Moreover, two-way analysis of variance (ANOVA) indicated that VSL#3 interacts with hMSCs to attenuate neurodegeneration and inhibit NLRP3 inflammasome-mediated inflammation without altering the effects of hMSCs. Major findings of our study support the usage of probiotic formulation VSL#3 as an adjuvant therapy to hMSC infusion in PD treatment. IMPORTANCE This study provides evidence for the neuroprotective activities of human umbilical cord MSCs from the aspect of anti-inflammation actions. hMSCs inhibit the NLRP3 inflammasome and MPTP-induced inflammation in both brain and periphery to relieve the degenerative changes in dopaminergic neurons in PD mice. Furthermore, as an additional therapeutic agent, probiotic formulation VSL#3 interacts with hMSCs in suppressing the NLRP3 inflammasome as well as the central and peripheral anti-inflammatory effects to exert neuroprotective actions in PD mice without altering the actions of hMSCs, suggesting the potential of VSL#3 as an adjuvant therapy in PD treatment. The findings of the present study give a further understanding of the anti-inflammatory activity and the molecular mechanism for the beneficial effects of MSCs as well as the potential application of probiotic formulation as an adjuvant approach to MSC therapy in PD treatment.

Apigenin attenuates LPS-induced neurotoxicity and cognitive impairment in mice via promoting mitochondrial fusion/mitophagy: role of SIRT3/PINK1/Parkin pathway

RationaleAlteration of the NAD+ metabolic pathway is proposed to be implicated in lipopolysaccharide (LPS)-induced neurotoxicity and mitochondrial dysfunction in neurodegenerative diseases. Apigenin, a naturally-occurring flavonoid, has been reported to maintain NAD+ levels and to preserve various metabolic functions.ObjectivesThis study aimed to explore the effect of apigenin on mitochondrial SIRT3 activity as a mediator through which it could modulate mitochondrial quality control and to protect against intracerebrovascular ICV/LPS-induced neurotoxicity.MethodsMice received apigenin (40 mg/kg; p.o) for 7 consecutive days. One hour after the last dose, LPS (12 µg/kg, icv) was administered.ResultsApigenin robustly guarded against neuronal degenerative changes and maintained a normal count of intact neurons in mice hippocampi. Consequently, it inhibited the deleterious effect of LPS on cognitive functions. Apigenin was effective in preserving the NAD+/NADH ratio to boost mitochondrial sirtuin-3 (SIRT3), activity, and ATP production. It conserved normal mitochondrial features via induction of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α), along with mitochondrial transcription factor A (TFAM) and the fusion proteins, mitofusin 2 (MFN2), and optic atrophy-1 (OPA1). Furthermore, it increased phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin expression as well as the microtubule-associated protein 1 light chain 3 II/I ratio (LC3II/I) to induce degradation of unhealthy mitochondria via mitophagy.ConclusionsThese observations reveal the marked neuroprotective potential of apigenin against LPS-induced neurotoxicity through inhibition of NAD+ depletion and activation of SIRT3 to maintain adequate mitochondrial homeostasis and function.Graphical abstract

Machine learning for analysis of gene expression data in fast- and slow-progressing amyotrophic lateral sclerosis murine models

Amyotrophic lateral sclerosis is a fatal motor neuron disease characterised by degenerative changes in both upper and lower motor neurons. Current treatment options in the general cohort of ALS patients have only a minimal impact on survival. Only two approved medications are available today, just addressing the management of symptoms and supporting the respiration. In this work, gene expression data from genetically modified murine motor neurons have been analysed with machine learning techniques, with the scope of distinguishing between mice developing a fast progression of the disease, and mice showing a slower progression. Results showed high accuracy (above 80%) in all tasks, with peaks of accuracy for specific ones – such as distinguishing between fast and slow progression. In the above mentioned task the best performing algorithm reached an accuracy of 100%. This research group is currently working on three more investigations on data from mice, using similar approaches and methodology, focusing on thoracic and lumbar metabolomic data as well as microbiome data. We believe that, based on the findings in the murine models, machine learning could be used to discover ALS progression markers in humans by looking at features related to the immune response. This could pave the path for the discovery of druggable targets and disease biomarkers for homogeneous ALS patient subgroups.

Degeneration Of Spinal Ganglion And Segmental Apparatus Of The Spinal Neurons In Sciatic Nerve Injury: An Experimental Study

Objective — To investigate the extent of degenerative changes in neurons of spinal ganglion and segmental apparatus in various injuries to sciatic nerve in the experiment on white rats. Material and Methods — The research involved 40 white non-pedigree male rats distributed among four groups. The animals of Group 1 (n=10) underwent the compression of nerve trunks with Mosquito clamp forceps for 15 minutes. In Group 2 (n=10), the animals had their nerve trunks ligated; and in Group 3, they had their nerves completely transected in their middle thirds. The separate group of control animals (n=10) suffered no damage to their sciatic nerves. Spinal cords and spinal ganglia at L4-L6 level were the material for histopathological examination. We calculated the number (percent) of degenerated neurons in spinal cords and spinal ganglia at the affected sides on Day 30, and compared them to those at the intact sides. Results — The number (percent) of degenerated neurons in spinal cord and spinal ganglion, expressed as Me (Q1; Q2), constituted 2.52% (1.92; 2.74) and 3.75% (2.37; 4.74) in Group 1, 9.27% (9.03; 9.94) and 16.74% (16.01; 18.22) in Group 2, 25.59% (24.36; 26.29) and 31.94% (31.44; 33.03) in Group 3, respectively. Depending on the number (percent) of degenerated neurons, we classified three grades of change manifestation: mild (Group 1), medium (Group 2), and severe (Group 3). No degenerated neurons were found in the control animals. Conclusion — The compression, ischemic exposure on the sciatic nerve, and complete anatomical transection of its trunk resulted in Wallerian degeneration, as well as degeneration of segmental apparatus in spinal cord neurons.

Robert's Intragastric Alcohol-Induced Gastric Lesion Model as an Escalated General Peripheral and Central Syndrome, Counteracted by the Stable Gastric Pentadecapeptide BPC 157.

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert’s model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 µg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment.

Structural aspects of the aging invertebrate brain.

Aging is characterized by a decline in neuronal function in all animal species investigated so far. Functional changes are accompanied by and may be in part caused by, structurally visible degenerative changes in neurons. In the mammalian brain, normal aging shows abnormalities in dendrites and axons, as well as ultrastructural changes in synapses, rather than global neuron loss. The analysis of the structural features of aging neurons, as well as their causal link to molecular mechanisms on the one hand, and the functional decline on the other hand is crucial in order to understand the aging process in the brain. Invertebrate model organisms like Drosophila and C. elegans offer the opportunity to apply a forward genetic approach to the analysis of aging. In the present review, we aim to summarize findings concerning abnormalities in morphology and ultrastructure in invertebrate brains during normal aging and compare them to what is known for the mammalian brain. It becomes clear that despite of their considerably shorter life span, invertebrates display several age-related changes very similar to the mammalian condition, including the retraction of dendritic and axonal branches at specific locations, changes in synaptic density and increased accumulation of presynaptic protein complexes. We anticipate that continued research efforts in invertebrate systems will significantly contribute to reveal (and possibly manipulate) the molecular/cellular pathways leading to neuronal aging in the mammalian brain.

The possible effect of coenzyme Q10 and captopril on acetaminophen-induced encephalopathy in rats: possible influence on autophagy, antioxidant and Na+/K+ ATPase

IntroductionInduction of autophagy could protect against acetaminophen (APAP)-induced hepatotoxicity; however, little is known about the role of autophagy in APAP-induced encephalopathy (APAP-E). This study aimed to evaluate the effects of coenzyme Q10 (CoQ10) and captopril on APAP-E.Material and methodsForty-eight rats were randomly allotted to 4 equal groups: control, an APAP-E, coenzyme Q10-treated (CoQ10-treated), and captopril-treated groups. Behavioral tests were conducted. Serum ammonia and total antioxidant capacity (TAC) and hippocampal Na+/K+ ATPase activity were measured. The expression levels of hippocampal microtubule-associated protein light chain 3 (LC3-II) and beclin-1 mRNA were detected using quantitative polymerase chain reaction (qPCR). General histological, immunohistochemical staining for glial fibrillary acid protein (GFAP) and electron microscopy (EM) of the hippocampus were performed.ResultsIn the APAP-E group, serum ammonia was increased significantly, hippocampal LC3-II and beclin-1 mRNA were elevated insignificantly, while serum TAC and the activity of hippocampal Na+/K+ ATPase were reduced significantly compared with the control group. APAP-E rats showed remarkable degenerative changes in CA1 pyramidal neurons in the form of electron-dense cytoplasm with ill-defined nuclei and accumulation of lysosomal structure-like dense bodies. Increased immunoreactivity of astrocytes for GFAP was observed. Treatment with either CoQ10 or captopril significantly reduced ammonia levels, increased hippocampal LC3-II and beclin-1 mRNA, increased serum TAC and Na+/K+ ATPase activity, and noticeably ameliorated the hippocampal neuronal changes. EM revealed restoration of the normal structure of pyramidal neurons. These effects were more obvious in CoQ10-treated than captopril-treated rats.ConclusionsCoQ10 and captopril have neuroprotective effects on APAP-E via enhancing LC3-II, beclin-1 mRNA expression, serum TAC level and hippocampal Na+/K+ ATPase activity.

Possible neurogenic mechanisms in sudden infant death syndrome

Background.Sudden infant death syndrome (SIDS) is the unexpected, non-violent death of an apparently healthy child aged 7 days to 1 year, in which the anamnesis and autopsy data do not reveal the cause of the fatal outcome. Researchers have not come to a consensus on the thanatological role of morphological changes in the brain.Aim.To determine pathomorphological changes in the brain in the case of sudden death syndrome in children.Material and methods.Forensic medical studies of 118 deaths of healthy children who died suddenly for the period 20082017 were carried out and analyzed on the territory of the Stavropol region. Autopsy material was divided into groups: the main group (1) consisted of 74 observations (62.8%), where SIDS was the main final sectional diagnosis. The comparison group (2) consisted of 44 (37.2%) observations; the children died suddenly at home as a result of viral-bacterial pneumonia. For the control, the third group was formed (3), which included 45 observations, where the death of children occurred as a result of drowning and carbon monoxide poisoning.Results.A histological examination of pieces of the brain in the case of sudden death syndrome revealed the foci of angiomatosis of the vessels of the pia mater and brain matter with the normal structure of the elastic membrane of the arteries, the effects of glial proliferation in the subependymal region of the lateral ventricles and subcortical formations. In the medulla oblongata, in a detailed study of the posterior (vegetative) nucleus of the vagus nerve, degenerative changes in neurons were detected in the form of chromatolysis and karyolysis, a glial reaction of the neuronophagic type.Conclusion.Pathomorphological changes in the brain stem may be due to combined intrauterine hypoxic and intrapartum traumatic factors, which, potentiating each other, lead to dysregulation of the respiratory rhythm with the development of a fatal outcome during sleep.

The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer's-Like Disease in Rats.

Alzheimer’s disease (AD) is a worldwide rapidly growing neurodegenerative disease. Here, we elucidated the neuroprotective effects of silymarin (SM) on the hippocampal tissues of aluminum chloride (AlCl3)-induced Alzheimer-like disease in rats using biochemical, histological, and ultrastructural approaches. Forty rats were divided into control, SM, AlCl3, and AlCl3 + SM groups. Biochemically, AlCl3 administration resulted in marked elevation in levels of lipid peroxidation (LPO) and nitric oxide (NO) and decrease in levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Moreover, AlCl3 significantly increased tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and acetylcholinesterase (AChE) activities. Furthermore, myriad histological and ultrastructural alterations were recorded in the hippocampal tissues of AlCl3-treated rats represented as marked degenerative changes of pyramidal neurons, astrocytes, and oligodendrocytes. Additionally, some myelinated nerve fibers exhibited irregular arrangement of their myelin coats, while the others revealed focal degranulation of their myelin sheaths. Severe defects in the blood–brain barrier (BBB) were also recorded. However, co-administration of SM with AlCl3 reversed most of the biochemical, histological, and ultrastructural changes triggered by AlCl3 in rats. The results of the current study indicate that SM can potentially mend most of the previously evoked neuronal damage in the hippocampal tissues of AlCl3-kindled rats.

Neonicotinoid-containing insecticide disruption of growth, locomotion, and fertility in Caenorhabditis elegans.

Neonicotinoids, a class of insecticides structurally similar to nicotine that target biting and sucking insects, are the most widely used insecticides today, in part due to their supposed low toxicity in other organisms. However, a growing body of research has found that even low doses of neonicotinoids can induce unexpected negative effects on the physiology and survival of a wide range of non-target organisms. Importantly, no work has been done on the commercial formulations of pesticides that include imidacloprid as the active ingredient, but that also contain many other components. The present study examines the sublethal effects of “Tree and Shrub”™ (“T+S”), a commercial insecticide containing the neonicotinoid imidacloprid as its active ingredient, on Caenorhabditis elegans. We discovered that “T+S” significantly stunted the overall growth in wildtype nematodes, an effect that was exacerbated by concurrent exposure to heat stress. “T+S” also negatively impacted fecundity as measured by increased germline apoptosis, a decrease in egg-laying, and fewer viable offspring. Lastly, exposure to “T+S” resulted in degenerative changes in nicotinic cholinergic neurons in wildtype nematodes. As a whole, these findings demonstrate widespread toxic effects of neonicotinoids to critical functions in nematodes.

Cerebral Pathology in Hepatolenticular Degeneration (Wilson Disease)

Introduction. Hepatolenticular degeneration (HLD), or Wilson disease, is one of the severe progressive hereditary disorders of the nervous system. A number of questions regarding its pathogenesis and pathology are the subject of in-depth research. The aim of the study was to examine cerebral pathology and determine the leading factors in its pathogenesis in the autopsy cases of HLD. Materials and methods. A postmortem study was carried out in 15 deceased patients (14–35 years old) with HLD. In all cases, clinical diagnosis was based on the characteristic signs of CNS and liver damage, presence of the Kayser–Fleischer corneal ring, and specific biochemical abnormalities in copper and protein metabolism. A set of histological, neurohistological, and histochemical staining methods was used, including the histochemical study of copper after the fixation of brain slices in rubeanic acid. Results. In all cases, severe microcirculatory changes were found in the brain, characteristic of the angiotoxic component of HLD, with impaired vessel permeability and the development of persistent edema and spongiform changes in brain tissue. Changes were more often found in the basal nuclei area, as well as in the white matter of the cerebral hemispheres, cerebellum, and pons. The cytotoxic component of HLD was evident in the same regions of the brain, represented by degenerative changes in astrocytes and neurons, often ending in their death. The most frequent form of pathology was the appearance of Alzheimer type II glia with ‘naked’ nuclei, and much less frequently, Alzheimer type I glia. The histochemical study showed deposits of copper granules in the endothelial cells of microvessels, Alzheimer type II glia, and neurons – predominantly in the globus pallidus and the caudate nucleus. Conclusion. A set of pathogenic factors plays an essential role in the pathogenesis of the brain damage in HLD: the toxic effect of copper on the brain, the damage to and impaired permeability of the blood-brain barrier, severe metabolic disturbances caused by liver failure, and brain hypoxia.

Ameliorative effect of Nigella sativa oil and vitamin C on the thyroid gland and cerebellum of adult male albino rats exposed to Monosodium glutamate (histological, immunohistochemical and biochemical studies)

Monosodium glutamate (MSG) is a major taste enhancer that is used as a food additive. Vitamin C (Vit C) and Nigella sativa oil (NSO) are known for their potent antioxidant activities. ObjectiveThis study investigates the adverse effect of MSG on the thyroid gland and cerebellum of adult male albino rats and the protection against MSG-mediated toxicity provided by Vit C and NSO. DesignFifty rats were divided into five groups that were treated via oral gavage. Group I (control) rats received distilled water, Group II rats were treated with MSG (6 mg/gm body weight/day), Group III rats were treated with MSG and Vit C (100 mg/kg body weight /day), Group IV rats were treated with MSG and NSO (50 mg/kg body weight two times per week), and Group V rats were treated with MSG together with both Vit C and NSO with MSG. After 60 days of treatment, rats were euthanized and histological sections were prepared from the thyroid gland and the cerebellum for routine staining and immunohistochemical detection of glial fibrillar acidic protein (GFAP), Caspase-3 and proliferating cell nuclear antigen (PCNA), respectively. Cerebellar tissue was also evaluated to determine glutathione (GSH) and malondialdehyde (MDA) levels; GSH was also measured in thyroid tissue. Serum levels of fT3, fT4 and TSH (thyroid stimulating hormone) were also evaluated. ResultsMicroscopic examination of cerebellar tissues revealed significant cerebellar injury and cellular apoptosis among the rats in Group II. The thyroid glands of Group II rats were notable for degenerating follicles, loss of colloid, sloughed follicular cells and congested blood vessels. The cerebellar and thyroid tissues from rats in treatment Groups III, IV and V revealed significantly less pathology. Cerebellar and thyroid tissues from Group II rats that were treated with MSG alone revealed intense GFAP and caspase-3 (cerebellar) and PCNA (thyroid) immunoreactivity. Furthermore, cerebellar tissues from rats received MSG alone (Group II) were notable for decreased levels of GSH and increased levels of MDA; thyroid tissue from rats in Group II also demonstrated decreased levels of GSH. Likewise, serum fT3 and fT4 levels were significantly decreased, while serum TSH was significantly increased among rats in Group II. Combined administration of Vit C and NSO together with MSG (Group V) revealed some variations in oxidative parameters compared to those in the Group I control rats. ConclusionsOral intake of MSG resulted in degenerative changes in neurons and astrocytes in cerebellum and, also degeneration of the thyroid glands of albino rats. Concomitant administration of Vit C and NSO may limit MSG-induced damage to the cerebellum and thyroid glands and thereby provide significant protection against the oxidative damage induced by MSG.