Necrotic Neurons Research Articles

Bifunctional halloysite nanotube-based Ripk1 siRNA delivery system rescues cognitive impairment by targeting amyloid β plaques for clearance and reducing necrotic neurons in Alzheimer’s disease mice

Alzheimer’s disease (AD) is exacerbated by abnormal accumulation of toxic β-amyloid (Aβ) aggregates and Aβ-mediated neuronal cell death. Currently, no effective drugs for AD treatment are mainly due to the blood–brain barrier hindrance, which limits the most drugs for application in AD treatment. Accumulating evidence suggests that increased levels of Ripk1 and enhancement of Ripk1-mediated neuronal necroptosis are known to play an important role in neuronal death in AD. Targeting Ripk1 by pharmacological or genetic inhibition of Ripk1 has been demonstrated to prevent neuronal necroptosis and improve memory deficits in AD mice models. Here, we showed that halloysite (HNTs), one of the nanoclays, absorbed Aβ and reduced toxic Aβ aggregate production by inhibiting fibril formation and promoting the clearance of Aβ plaques. We also presented evidence that RVG29, a brain-penetrating peptide, bound directly to Aβ species and inhibited Aβ aggregation. In addition, Ripk1 is more dramatically expressed around Aβ plaques than those far from plaques in the brain of AD mice. Therefore, we designed a novel Aβ plaque-targeted nanomedicine (SH-RVG/siRipk1) via functionalizing with RVG29 onto short HNTs (SH) and loading Ripk1 siRNA (siRipk1) into the lumen of SH to prevent siRipk1 degradation. As we expected, SH-RVG/siRipk1 not only reduced plaques and improved memory impairment but also rescued necrotic neuronal loss around plaques by reducing Ripk1 expression around plaques in AD mice. These findings indicate that SH-RVG/siRipk1 may be an effective strategy for the treatment of AD.

Studies on the sequential pathology of Kyasanur Forest Disease (KFD) in Mouse brain: KFD virus induces apoptosis of neurons in cerebrum and hippocampus.

The sequential pathology of Kyasanur forest disease (KFD) in mouse brain was assessed in this study. Kyasanur forest disease virus (KFDV) strain P9605 used in this study was confirmed by real-time reverse transcriptase-polymerase chain reaction targeting the NS5 gene. Mouse Lethal Dose 50 (MLD50) of the virus was determined by in-vivo mice inoculation test. One MLD50 of the KFDV was inoculated intra-cerebrally into 36 mice aged 2-3 weeks. Another group of 36 age-matched mice that served as control group were inoculated with plain media. Six mice each from infected and control groups were euthanized every 24 hrs intervals for six days. Brain tissues were collected in 10% NBF. The collected brain tissues were processed and subjected to histopathological studies by Hematoxylin and Eosin staining. Grossly, the infected mice showed symptoms of dullness, hunched back appearance, weakness, sluggish movements with indication of hind quarter paralysis on day four post-infection. These symptoms got aggravated with complete paralysis of the hind quarters, inability to move and death on 5th and 6th day post-infection. Microscopically, the brain showed apoptosis of neurons, perivascular cuffing, gliosis, congestion, neuropil vacuolation, meningitis, degeneration, and necrotic neurons. The real-time RT-PCR on hippocampus of the KFDV-infected mouse brain showed three-fold higher expression levels of Caspase 3, a crucial mediator of apoptosis. The cerebral cortex, cerebellum and hippocampus that control the motor neuron activities and muscle tone were primarily affected, possibly correlating with the gross symptoms of hind quarter paralysis, ataxia, and other motor neuron dysfunctions noticed. Taken together, these findings reveal that KFDV induces apoptosis of neurons in the cerebrum and hippocampus of KFDV infected mice. Further studies are needed to confirm if the lesions noticed in mice brain simulate the brain lesions in humans since gross motor-neuron symptoms are similar in mice as well as humans.

Effect of electroacupuncture of Governor Vessel on mitochondrial fusion and proliferation and differentiation of neural stem cells in spinal cord injury rats.

To observe the effect of electroacupuncture (EA) at "Dazhui" (GV14) and "Jizhong"(GV6) of the Governor Vessel (GV) on mitochondrial fusion and neural stem cell (NSC) proliferation and differentiation in the spinal cord of rats with spinal cord injury (SCI), so as to investigate its mechanisms underlying improvement of SCI. SD rats were randomly divided into sham operation, model and EA groups, with 15 rats in each group. The SCI model was established by using a precision impactor. EA (20 Hz/100 Hz, 1-2 mA) was applied to GV14 and GV6 for 30 min, once daily for 14 days. The rats' hindlimb locomotor function in each group was assessed using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Histopathological changes of the injured spinal cord tissue and the number of neurons were evaluated after H.E. staining and Nissl staining. The expressions of Nestin, mitochondrial fusion-related protein optic atrophy-1 (OPA1) and NSC markers sex-determining region Y-box 2 (SOX2) in the injured spinal cord tissue were detected by immunofluorescence staining. The protein and mRNA expression levels of Nestin in the spinal cord tissue were detected by quantitative real-time PCR and Western blot, separately. Compared with the sham operation group, the BBB scores after modeling, and the number of neurons were significantly decreased (P<0.001), while the mean fluorescence intensity values of Nestin, SOX2 and OPA1, and the expressions of Nestin mRNA and protein considerably increased (P<0.001, P<0.01, P<0.05) in the model group. After EA intervention and in comparison with the model group, the BBB scores at the 7th and 14th day, the number of neurons, the mean fluorescence intensity values of Nestin, SOX2 and OPA1, and the expressions of Nestin mRNA and protein were strikingly increased (P<0.05, P<0.01, P<0.001) in the EA group. H.E. staining showed swollen, ruptured and necrotic neurons of the spinal cord, with a large number of vacuoles and severe inflammatory cell infiltration after modeling, which was relatively milder in the EA group. EA stimulation of GV14 and GV6 can promote the recovery of motor function in rats with SCI, which may be related to its effects in promoting mitochondrial fusion and enhancing the proliferation and differentiation of NSCs.

Role of microglia in stroke.

Microglia play key roles in the post-ischemic inflammatory response and damaged tissue removal reacting rapidly to the disturbances caused by ischemia and working to restore the lost homeostasis. However, the modified environment, encompassing ionic imbalances, disruption of crucial neuron-microglia interactions, spreading depolarization, and generation of danger signals from necrotic neurons, induce morphological and phenotypic shifts in microglia. This leads them to adopt a proinflammatory profile and heighten their phagocytic activity. From day three post-ischemia, macrophages infiltrate the necrotic core while microglia amass at the periphery. Further, inflammation prompts a metabolic shift favoring glycolysis, the pentose-phosphate shunt, and lipid synthesis. These shifts, combined with phagocytic lipid intake, drive lipid droplet biogenesis, fuel anabolism, and enable microglia proliferation. Proliferating microglia release trophic factors contributing to protection and repair. However, some microglia accumulate lipids persistently and transform into dysfunctional and potentially harmful foam cells. Studies also showed microglia that either display impaired apoptotic cell clearance, or eliminate synapses, viable neurons, or endothelial cells. Yet, it will be essential to elucidate the viability of engulfed cells, the features of the local environment, the extent of tissue damage, and the temporal sequence. Ischemia provides a rich variety of region- and injury-dependent stimuli for microglia, evolving with time and generating distinct microglia phenotypes including those exhibiting proinflammatory or dysfunctional traits and others showing pro-repair features. Accurate profiling of microglia phenotypes, alongside with a more precise understanding of the associated post-ischemic tissue conditions, is a necessary step to serve as the potential foundation for focused interventions in human stroke.

Memantine protects the cultured rat hippocampal neurons treated by NMDA and amyloid β1-42.

Alzheimer's disease (AD) is a devastating neurodegenerative condition with no effective treatments. Recent research highlights the role of NMDA receptors in AD development, as excessive activation of these receptors triggers excitotoxicity. Memantine, an NMDA receptor antagonist, shows promise in curbing excitotoxicity. What sets our study apart is our novel exploration of memantine's potential to protect hippocampal neurons from neurotoxicity induced by NMDA and amyloid β1-42, a hallmark of AD. To achieve this, we conducted a series of experiments using rat hippocampal cell cultures. We employed Hoechst and propidium iodide double staining to assess neuronal viability. Analyzing the viability of neurons in normal conditions compared to their status after 24 h of exposure to the respective agents revealed compelling results. The incubation of hippocampal neurons with NMDA or amyloid β1-42 led to a more than twofold increase in the number of apoptotic and necrotic neurons. However, when memantine was co-administered with NMDA or amyloid β1-42, we witnessed a notable augmentation in the number of viable cells. This unique approach not only suggests that memantine may act as a neuroprotective agent but also emphasizes the relevance of hippocampal neuron cultures as valuable models for investigating excitotoxicity and potential AD treatments.

Anabolic Androgenic Steroid predisposes to the neuropathology of Alzheimer’s disease: insights from Animal model

AbstractBackgroundAnabolic androgenic steroids (AASs) are synthetic derivatives of testosterone use for body enhancement by athletes and its use has been abused over the years. Various studies have reported the harmful potential of AAS use, however, there is need to document its possibility as a risk factor in neuropathology of dementia. This study is to demonstrate potential of AAS as a risk factor in Alzheimer’s disease (AD) pathology by demonstrating changes in the neuro‐morphology, astrocytic proliferation and neurofibrillary tangle formation in animal model.MethodTwenty (20) adult male Wistar rats used were divided into four groups (A‐D), treated as follows, Control (A), Olive oil as vehicle (B), oral 120mg/kg of AAS for 21days (C), and 7 days withdrawal group following 120mg/kg/ 21days of AAS intake (D). Serum was assayed for lipid peroxidation marker Malondialdehyde (MDA) and antioxidant enzyme ‐superoxide Dismutase (SOD). The prefrontal cortices were processed and stained for Nissl (chromatophilic) bodies, astrocytes immunohistochemistry and Bielschowsky stain for neurofibrillary tangles.ResultAAS treated group has characteristic pathology of AD demonstrated by the presence of necrosis, chromatolysis, marked astrocytic proliferation and presence of neurofibrillary tangles using Bielschowsky stain along with an increase in MDA and decline in endogenous SOD activities as compared with the control and olive oil treated groups. The withdrawal group (D) had a notable or mild restoration of the neurons demonstrated by presence of few necrotic neurons, reduced reactive astrocytes (astrogliosis) proliferation, decline in MDA with an increase in SOD when compared to the AAS treated group.ConclusionAAS has the potential to predispose individual to the neuropathology of AD characterized by neurodegeneration, astrogliosis, neurofibrillary tangles even in the presence of endogenous antioxidant enzyme, however, upon discontinuation endogenous antioxidant enzyme level increases enabling neuro repair via mobbing off free radicals generated by AAS.

Protective effect of melatonin on blood-brain barrier damage caused by Endotoxemia

ABSTRACT Objective Endotoxins, products of Gram-negative bacteria, are the primary cause of blood-brain barrier (BBB) damage. In the present study, we aimed to investigate the possible neuroprotection mechanisms of melatonin on BBB damage induced by endotoxemia. Methods Adult, female Sprague-Dawley rats (n = 42) were separated into four random groups as a control group and three treatment groups. Lipopolysaccharide (7,5 mg/kg/day) was administrated for a single dose to generate a 24-hour sepsis model on rats. Melatonin (10 mg/kg/day) was treated a week before sepsis. Afterward, the dissected brain tissues were examined by histopathological, biochemical, and molecular analyses. Results LPS caused weight loss in the groups. As a result, degenerated neurons with cytoplasmic vacuoles and irregular pyknotic nuclei, pale stained necrotic neurons, and vascular congestion were observed in LPS-exposed rats. However, MEL decreased the number of degenerated neurons in treated groups. MEL treatment increased ZO1 and Occludin immunoreactivity while decreasing TLR4 in brain tissues. MEL effect on protein expression was recorded for ZO1 increase and TLR4 decrease in brain tissue compared to LPS groups. MEL also decreased MDA levels in brain tissue. Conclusions MEL recovered the degenerative damage of sepsis by contributing to blood-brain barrier integrity, and by decreasing inflammation, thus the neuroprotective effects of MEL might provide an experimental basis for clinical applications.

ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2.

Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1α (IRE1α), leading toactivation of caspase-2, cleavage of the pro-apoptotic protein BH3-interacting domain death agonist (BID), and mitochondria-dependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDME-mediated cell death and promote inflammation.

Kalirin is involved in epileptogenesis by modulating the activity of the Rac1 signaling pathway

Background and objectiveEpilepsy is a common chronic brain disease. Despite the availability of various anti-seizure drugs, approximately 30 % of patients do not respond to treatment. Recent research suggests that Kalirin plays a role in regulating neurological function. However, the pathogenesis of Kalirin in epileptic seizures remains unclear. This study aims to investigate the role and mechanism of Kalirin in epileptogenesis. Materials and methodsAn epileptic model was induced by intraperitoneal injection of pentylenetetrazole (PTZ). Endogenous Kalirin was inhibited using shRNA. The expression of Kalirin, Rac1, and Cdc42 in the hippocampal CA1 region was measured using Western blotting. Spine and synaptic structures were examined using Golgi staining and electron microscopy. Moreover, the necrotic neurons in CA1 were examined using HE staining. ResultsThe results indicated that the epileptic score increased in epileptic animals, while inhibition of Kalirin decreased the epileptic scores and increased the latent period of the first seizure attack. Inhibition of Kalirin attenuated the increases in Rac1 expression, dendritic spine density, and synaptic vesicle number in the CA1 region induced by PTZ. However, the increase in Cdc42 expression was not affected by the inhibition of Kalirin. ConclusionThis study suggests that Kalirin is involved in the development of seizures by modulating the activity of Rac1, providing a novel anti-epileptic target.

The effect of cerium dioxide nanoparticles on the viability of hippocampal neurons in Alzheimer's disease modeling.

The possibilities of using nanoparticle materials based on cerium dioxide (CNPs) are exciting since they are low toxic and have specific redox, antiradical properties. It can be supposed that CNPs' biomedical use is also relevant in neurodegenerative diseases, especially Alzheimer's disease (AD). AD is known as the pathologies leading to progressive dementia in the elderly. The factor that provokes nerve cell death and cognitive impairment in AD is the pathological accumulation of beta-amyloid peptide (Aβ) in the brain tissue. In our studies, we examined the impact of Aβ 1-42 on neuronal death and evaluated the potential neuroprotective properties of CNPs during AD modeling in cell culture. Our findings show that, under AD modeling conditions, the number of necrotic neurons increased from 9.4% in the control to 42.7% when Aβ 1-42 was used. In contrast, CNPs alone showed low toxicity, with no significant increase in the number of necrotic cells compared to control conditions. We further explored the potential of CNPs as a neuroprotective agent against Aβ-induced neuronal death. We found that introducing CNPs 24 h after Aβ 1-42 incubation or prophylactically incubating hippocampal cells with CNPs 24 h before amyloid administration significantly reduced the percentage of necrotic cells to 17.8 and 13.3%, respectively. Our results suggest that CNPs in the cultural media can significantly reduce the number of dead hippocampal neurons in the presence of Aβ, highlighting their neuroprotective properties. These findings suggest that CNPs may hold promise for developing new treatments for AD based on their neuroprotective properties.

Effect of Dose-Related Astaxanthin on Rats with Cerebral Ischemia-Reperfusion

Introduction: The prevalence of cerebral ischemia-related diseases, which mostly affect the brain, has become pervasive and is associated with significant societal and economic challenges. The deficiency of the organism’s antioxidant defense system results in an elevation of free radicals, which in turn contributes to the development of a range of illnesses and aging processes, with a particular emphasis on cancer. The objective of our research was to examine the potential protective impact of astaxanthin (AST) on the antioxidant system inside the brain. Material and Method: Within the experimental framework, a total of 32 male rats were utilized, with each group consisting of 8 rats separated into 4 subgroups. Dimethyl sulfoxide and AST were delivered intraperitoneally to the rats 30 minutes before to the surgery. A 15-minute period of ischemia was conducted. After a period of 24 hours of reperfusion, the rats underwent decapitation. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) levels were analyzed and brain sections were examined. Results: A significant decrease in the levels of SOD and CAT was observed in the sham group, while a significant increase was observed in the group treated with AST. This indicates that the antioxidant defense system is insufficient against the free radicals that increase after ischemia, while AST has a significant protective effect on the antioxidant system. The significant increase in MDA levels in the sham group suggests that oxidative damage occurs in the brain. In the groups administered AST, we observed a significant decrease. This indicates to us that AST has an extensive protective effect on the brain at high doses. In the sham group, significant damage and a high number of necrotic neurons were observed in the cerebral cortex. Neurons with less damage were observed in the groups treated with AST. The histological data suggest that AST may have a limited neuroprotective effect. Conclusion: The results show that AST has some preventive effect in reducing oxidative damage and against brain damage. In order to increase the objectivity and clarity of the histological evaluations, it will be useful to perform quantitative analyzes and evaluations and to categorize the detected changes. Keywords: Ischemia-reperfusion, common carotid artery, free radicals, antioxidants, astaxanthin, tissue damage.

Effect of electroacupuncture at Baihui ameliorated neurologic deficit and hemodynamic stability in rat model of post-cardiac arrest syndrome

To observe the results of electroacupuncture (EA) on the resuscitation of a rat model of asphyxia cardiac arrest (CA). And to explore its effect on the neurologic deficits and hemodynamic instability of post-cardiac arrest syndrome (PCAS). A total of 107 male SD rats were randomly divided into sham, CA, and EA groups. Each group received arterial catheterization and tracheal intubation. The sham group was not induced asphyxia. Asphyxial cardiac arrest was established by endotracheal tube clamping. Rats in the CA group received basic respiratory support and fluid resuscitation in return of spontaneous circulation (ROSC) and rats in the EA group received EA at Baihui based on the treatment of CA group after ROSC, with a dense-dispersed wave at frequencies of 4-20 Hz, while the current intensity was adjusted minimum to induce a twitch of the scalp, the course of treatment was 30 minutes. The baseline data, hemodynamics after ROSC, neurological deficit score (NDS), pathological changes of brain tissue, and levels of serum biomarker were recorded and compared among the three groups. The 72-hour survival of rats was analyzed by Kaplan-Meier survival curve. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of necrotic neurons in the hippocampal CA1 region of rat brain. Meanwhile, Nissl staining and TdT-mediated dUTP nick-end labeling (TUNEL) were used to detect cell apoptosis and injury. Compared with the CA group, the mean arterial pressure (MAP) in the EA group increased significantly at 15 minutes after ROSC [mmHg (1 mmHg ≈ 0.133 kPa): 125.00 (94.00, 136.25) vs. 92.00 (72.00, 122.50), P < 0.05]. There was no significant difference in the NDS score between the EA group and the sham group. Still, the NDS score of the rats in the CA group at 6 hours after ROSC were significantly lower than that in the sham group (46.00±10.61 vs. 80.00±0.00, P < 0.05). Kaplan-Meier survival curve analysis showed that EA did not improve the 72-hour survival rate of rats (100% in the sham group, 25% in the CA group, and 30% in the EA group, P > 0.05). The analysis by TUNEL showed that the apoptosis rate of neurons in CA1 region of the hippocampus in EA group at 6 hours after ROSC was significantly lower than that in CA group [(62.84±2.67)% vs. (71.29±3.70)%, P < 0.05]. Compared with the CA group, the level of serum S100 calcium binding protein B (S100B) in the EA group at 6 hours after ROSC was significantly lower (ng/L: 19.30±13.87 vs. 132.28±31.67, P < 0.05), but there were no significant differences in the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) between these two groups. In the present study, EA at Baihui can stabilize the hemodynamic, moreover, it has a particular neuroprotective effect on PCAS rats. Still, EA at Baihui does not reduce the systemic inflammatory response and improve the survival rate of rats, and its mechanism remains to be verified in further research.

Determining the effects of in ovo administration of monosodium glutamate on the embryonic development of brain in chickens

Monosodium glutamate (MSG) is a popular flavor enhancer largely used in the food industry. Although numerous studies have reported the neurotoxic effects of MSG on humans and animals, there is limited information about how it affects embryonic brain development. Thus, this study aimed to determine the effects of in ovo administered MSG on embryonic brain development in chickens. For this purpose, 410 fertilized chicken eggs were divided into 5 groups as control, distilled water, 0.12, 0.6 and 1.2 mg/g egg MSG, and injections were performed via the egg yolk. On days 15, 18, and 21 of the incubation period, brain tissue samples were taken from all embryos and chicks. The mortality rates of MSG-treated groups were significantly higher than those of the control and distilled water groups. The MSG-treated groups showed embryonic growth retardation and various structural abnormalities such as abdominal hernia, unilateral anophthalmia, hemorrhage, brain malformation, and the curling of legs and fingers. The relative embryo and body weights of the MSG-treated groups were significantly lower than those of the control group on incubation days 18 and 21. Histopathological evaluations revealed that MSG caused histopathological changes such as necrosis, neuronophagia, and gliosis in brain on incubation days 15, 18, and 21. There was a significant increase in the number of necrotic neurons in the MSG-treated groups compared to the control and distilled water groups in the hyperpallium, optic tectum and hippocampus regions. Proliferating cell nuclear antigen (PCNA) positive cells in brain were found in the hyperpallium, optic tectum, and hippocampus regions; there were more PCNA(+) immunoreactive cells in MSG-treated groups than in control and distilled water groups. In conclusion, it was determined that in ovo MSG administered could adversely affect embryonic growth and development in addition to causing necrosis in the neurons in the developing brain.

Mechanism of Huangqi–Honghua combination regulating the gut microbiota to affect bile acid metabolism towards preventing cerebral ischaemia–reperfusion injury in rats

Context Effective treatment of ischaemic stroke is required to combat its high prevalence and incidence. Although the combination of Astragalus membranaeus (Fisch.) Bge. (Fabaceae) and Carthamus tinctorius L. (Asteraceae) is used in traditional Chinese medicine for the treatment of stroke, its underlying mechanism remains unclear. Objective The objective of this study is to elucidate the mechanism underlying Huangqi-Honghua (HQ-HH) for the treatment of ischaemic stroke by gut microbiota analysis and metabonomics. Materials and methods Sprague–Dawley rats were randomly assigned to the sham, model, HQ-HH, and Naoxintong (NXT) groups. The middle cerebral artery occlusion-reperfusion model was established after 7 days of intragastric administration in the HQ-HH (4.5 g/kg, qd) and NXT (1.0 g/kg, qd) groups. The neurological examination, infarct volume, gut microbiota, bile acids, and inflammation markers were assessed after 72 h of reperfusion. Results Compared with the model group, HQ-HH significantly reduced the neurological deficit scores of the model rats (2.0 ± 0.2 vs. 3.16 ± 0.56), and reduced the cerebral infarct volume (27.83 ± 3.95 vs. 45.17 ± 2.75), and reduced the rate of necrotic neurons (26.35 ± 4.37 vs. 53.50 ± 9.61). HQ-HH regulating gut microbiota, activating the bile acid receptor FXR, maintaining the homeostasis of bile acid, reducing Th17 cells and increasing Treg cells in the rat brain, reducing the inflammatory response, and improving cerebral ischaemia–reperfusion injury. Conclusions These data indicate that HQ-HH combination can improve ischaemic stroke by regulating the gut microbiota to affect bile acid metabolism, providing experimental evidence for the wide application of HQ-HH in clinical practice of ischaemic stroke.

Alzheimer's disease as an innate autoimmune disease (AD2): A new molecular paradigm.

A new model of Alzheimer's disease (AD) is presented: Alzheimer's disease as an autoimmune disease (AD2). In response to pathogen-/damage-associated molecular pattern-stimulating events (e.g.,infection, trauma, ischemia,pollution), amyloid beta (Aβ) is released as an early responder cytokine triggering an innate immunity cascade in which Aβ exhibits immunomodulatory/antimicrobial duality. However, Aβ's antimicrobial properties result in a misdirected attack upon "self" neurons, arising from the electrophysiological similarities between neurons and bacteria in terms of transmembrane potential gradients and anionic charges on outer membrane macromolecules. The subsequent breakdown products of necrotic neurons elicit further release of Aβ leading to a chronic, self-perpetuating cycle. In AD2, amino acid (trp, arg) metabolism is a central control player in modulating AD autoimmunity.AD2 includes Aβ as an important molecular player, butrejects the "amyloid hypothesis," recognizing Aβ as a physiologically oligomerizing cytokine andpart of a larger immunopathic conceptualization of AD.

Visual hallucinations in dementia with Lewy bodies originate from necrosis of characteristic neurons and connections in three-module perception model

Mathematical and computational approaches were used to investigate dementia with Lewy bodies (DLB), in which recurrent complex visual hallucinations (RCVH) is a very characteristic symptom. Beginning with interpretative analyses of pathological symptoms of patients with RCVH-DLB in comparison with the veridical perceptions of normal subjects, we constructed a three-module scenario concerning function giving rise to perception. The three modules were the visual input module, the memory module, and the perceiving module. Each module interacts with the others, and veridical perceptions were regarded as a certain convergence to one of the perceiving attractors sustained by self-consistent collective fields among the modules. Once a rather large but inhomogeneously distributed area of necrotic neurons and dysfunctional synaptic connections developed due to network disease, causing irreversible damage, then bottom-up information from the input module to both the memory and perceiving modules were severely impaired. These changes made the collective fields unstable and caused transient emergence of mismatched perceiving attractors. This may account for the reason why DLB patients see things that are not there. With the use of our computational model and experiments, the scenario was recreated with complex bifurcation phenomena associated with the destabilization of collective field dynamics in very high-dimensional state space.

Effects of subacute cadmium exposure and subsequent deferiprone treatment on cadmium accumulation and on the homeostasis of essential elements in the mouse brain

IntroductionCadmium (Cd) is а hazardous multi-organ toxin. In this study, we provide the first results about the effect of oral administration of deferiprone (DFP) on Cd accumulation and on the homeostasis of essential elements in the brain of Cd-exposed mice. MethodsAdult Institute of Cancer Research (ICR) male mice were randomized into four experimental groups: untreated controls – administered distilled water for 28 days; Cd-exposed group – exposed to 18 mg/kg body weight (b.w.) Cd(II) acetate for 14 days followed by the administration of distilled water for two weeks; Cd + DFP (low dose) – Cd-intoxicated mice subsequently treated with 19 mg/kg b.w. DFP for two weeks; and Cd + DFP (high dose) – Cd-exposed mice administered high-dose DFP (135 mg/kg b.w.) for 14 days. Brains were subjected to inductively coupled plasma-mass spectrometry (ICP-MS) and histological analysis. ResultsThe results revealed that exposure of mice to Cd for 14 days significantly increased Cd concentration and significantly decreased magnesium (Mg), phosphorus (P), and zinc (Zn) contents in the brain compared to untreated controls. This effect was accompanied by necrotic-degenerative changes in both the cerebrum and cerebellum. Oral administration of low-dose DFP to Cd-exposed mice decreased the concentration of the toxic metal in the brain by 16.37% and restored the concentration of the essential elements to normal control values. Histological analysis revealed substantially improved cerebral and cerebellar histoarchitectures. In contrast, oral administration of high-dose DFP increased Cd content and significantly decreased selenium (Se) concentration in the brain. Necrotic neurons and Purkinje cells were still observed in the cerebral and cerebellar cortices. ConclusionThe results demonstrated that oral administration of DFP at low doses has a better therapeutic potential for the treatment of Cd-induced brain damage compared to high doses.

Long-Term Sequelae of COVID-19 in Experimental Mice

We recently reported acute COVID-19 symptoms, clinical status, weight loss, multi-organ pathological changes, and animal death in a murine hepatitis virus-1 (MHV-1) coronavirus mouse model of COVID-19, which were similar to that observed in humans with COVID-19. We further examined long-term (12 months post-infection) sequelae of COVID-19 in these mice. Congested blood vessels, perivascular cavitation, pericellular halos, vacuolation of neuropils, pyknotic nuclei, acute eosinophilic necrosis, necrotic neurons with fragmented nuclei, and vacuolation were observed in the brain cortex 12 months post-MHV-1 infection. These changes were associated with increased reactive astrocytes and microglia, hyperphosphorylated TDP-43 and tau, and a decrease in synaptic protein synaptophysin-1, suggesting the possible long-term impact of SARS-CoV-2 infection on defective neuronal integrity. The lungs showed severe inflammation, bronchiolar airway wall thickening due to fibrotic remodeling, bronchioles with increased numbers of goblet cells in the epithelial lining, and bronchiole walls with increased numbers of inflammatory cells. Hearts showed severe interstitial edema, vascular congestion and dilation, nucleated red blood cells (RBCs), RBCs infiltrating between degenerative myocardial fibers, inflammatory cells and apoptotic bodies and acute myocyte necrosis, hypertrophy, and fibrosis. Long-term changes in the liver and kidney were less severe than those observed in the acute phase. Noteworthy, the treatment of infected mice with a small molecule synthetic peptide which prevents the binding of spike protein to its respective receptors significantly attenuated disease progression, as well as the pathological changes observed post-long-term infection. Collectively, these findings suggest that COVID-19 may result in long-term, irreversible changes predominantly in the brain, lung, and heart.

Dietary Feeding Lycopene, Citric Acid, and Chlorella Alleviated the Neurotoxicity of Polyethylene Microplastics in African Catfish (Clarias gariepinus)

A few studies assessed how natural products can protect fish from the neurotoxic effects of Microplastics (MPs). Therefore, the goal of this study was to look into the neurotoxicity of PE-MPs on the brain tissue of African catfish (C. gariepinus), and whether dietary feeding on Chlorella, citric acid, and lycopene could help alleviate their toxicity. Five groups of fish were used: The first group received a standard diet (control). The second group was fed 500 mg/kg PE-MP. The third group was fed PE-MP + lycopene (500 mg/kg diet). The fourth group was fed PE-MP + citric acid (30 g/kg diet). And the fifth group was fed PE-MP + Chlorella (50 g/kg diet) for 15 days. The activities of Acetylcholinesterase (Ach), Monoamine Oxidase (MAO), Aldehyde Oxidase (AO), and Nitric Oxide (NO), and the histological effect on brain tissues were then assessed. The activity of the four neurological biomarker enzymes investigated was altered significantly in fish subjected to PE-MP alone compared with the control group. For fish exposed to PE-MP with lycopene, citric acid, or Chlorella, the activities of these neurological enzymes significantly improved particularly with Chlorella compared with fish fed PE-MP individually. Histological investigations illustrated that being subjected to PE-MPs effected cellular alterations in the telencephalon, including diffuse distorted and degraded neurons, encephalomalacia, aggregated neuroglial cells (gliosis), as well as deformed and necrotic neurons, neuropil vacuolation (spongiosis), aggregated neuroglial cells (gliosis), pyknotic neurons, and shrunken Purkinje cells which were found in the cerebellum. Most histological alterations induced by exposure to PE-MP feeding were restored by dietary feeding on Chlorella, citric acid, and lycopene. Accordingly, this study recommends using citric acid, lycopene, and Chlorella as a natural remedy against MP neurotoxicity particularly with Chlorella.

Beta-Boswellic Acid Protects Against Cerebral Ischemia/Reperfusion Injury via the Protein Kinase C Epsilon/Nuclear Factor Erythroid 2-like 2/Heme Oxygenase-1 Pathway.

Ischemic strokes are associated with a high rate of disability and death globally. Cerebral ischemia/reperfusion (I/R) injury is a type of brain damage associated with oxidative stress after an ischemic stroke. Beta-boswellic acid (β-BA) reportedly exerts antioxidant and neuroprotective effects, but its role in cerebral I/R injury is unclear. The aim of this research was to investigate the neuroprotective effects, as well as the mechanisms of β-BA in cerebral I/R injury. In vivo experiments were conducted using a rat middle cerebral artery occlusion and reperfusion (MCAO/R) model, and in vitro experiments were performed using a rat neuronal oxygen-glucose deprivation and reoxygenation (OGD/R) model. Triphenyltetrazolium chloride staining, neurological function scores, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling, hematoxylin and eosin staining, and antioxidant levels in the brain were used to assess the effects of β-BA. Flow cytometry was used to detect reactive oxygen species and apoptotic cells. Western blotting and immunofluorescence staining were used to measure protein levels. The results showed that β-BA markedly improved neurological deficits and decreased infarct volume and necrotic neurons in rats. The in vitro results showed that β-BA protected neurons against OGD/R-induced injury. Additionally, β-BA significantly increased the phosphorylation of protein kinase C epsilon (PRKCE) at S729, the translocation of nuclear factor erythroid 2-like 2 (NFE2L2), and expression of heme oxygenase-1 (HMOX1). This study demonstrates that β-BA exerts neuroprotective effects against cerebral I/R via the activation of the PRKCE/NFE2L2/HMOX1 pathway and is a potential therapeutic candidate for ischemic stroke.