Ischemic penumbra in retina endures： vascular neuropathology is reconciled

A physiological state of＂normoxia＂obtains when tissue oxygen tension（pO_2）is sufficient to drive mitochondrial respiration throughout a volume of cells.Between 30-40%of the available oxygen is normally extracted from hemoglobin as it passes through neural tissue.

NLRP3-dependent pyroptosis is required for HIV-1 gp120- induced neuropathology

The human immunodeficiency virus-1(HIV-1)envelope protein gp120 is the major contributor to the pathogenesis of HIVassociated neurocognitive disorder(HAND).Neuroinflammation plays a pivotal role in gp120-induced neuropathology,but how gp120 triggers neuroinflammatory processes and subsequent neuronal death remains unknown.Here,we provide evidence that NLRP3 is required for gp120-induced neuroinflammation and neuropathy.Our results showed that gp120-induced NLRP3-dependent pyroptosis and IL-1βproduction in microglia.Inhibition of microglial NLRP3 inflammasome activation alleviated gp120-mediated neuroinflammatory factor release and neuronal injury.Importantly,we showed that chronic administration of MCC950,a novel selective NLRP3 inhibitor,to gp120 transgenic mice not only attenuated neuroinflammation and neuronal death but also promoted neuronal regeneration and restored the impaired neurocognitive function.In conclusion,our data revealed that the NLRP3 inflammasome is important for gp120-induced neuroinflammation and neuropathology and suggest that NLRP3 is a potential novel target for the treatment of HAND.

Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms

Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.

Neuropathology

2008113 Experimental study of the apoptosis in rat hippocampus induced by high iodine. YUE Dan(岳丹), et al. Dept Biochem, Liaoning Med Coll, Jinzhou 121001. Chin J Endemiol 2007;26(6):611-615. Objective To investigate the morphological structure and the mechanism of the apoptosis in rat hippocampus induced by high iodine. Methods An animal model of goiter was reconstructed in rat fed with water containing high level of iodine

Security breach:peripheral nerves provide unrestricted access for toxin delivery into the central nervous system

We explore the hypothesis that a potential explanation for the initiation of motor neuron disease is an unappreciated vulnerability in central nervous system defense,the direct delivery of neurotoxins into motor neurons via peripheral nerve retrograde transport.This further suggests a mechanism for focal initiation of neuro-degenerative diseases in general,with subsequent spread by network degeneration as suggested by the Frost-Diamond hypothesis.We propose this vulnerability may be a byproduct of vertebrate evolution in a benign aquatic environment,where external surfaces were not exposed to concentrated neurotoxins.

Gut dysbiosis aggravates cognitive deficits,amyloid pathology and lipid metabolism dysregulation in a transgenic mouse model of Alzheimer's disease

Gut dysbiosis,a well-known risk factor to triggers the progression of Alzheimer's disease(AD),is strongly associated with metabolic disturbance.Trimethylamine N-oxide(TMAO),produced in the dietary choline metabolism,has been found to accelerate neurodegeneration in AD pathology.In this study,the cognitive function and gut microbiota of TgCRND8(Tg)mice of different ages were evaluated by Morris water maze task(MWMT)and 16S rRNA sequencing,respectively.Young pseudo germ-free(PGF)Tg mice that received faecal microbiota transplants from aged Tg mice and wild-type(WT)mice were selected to determine the role of the gut microbiota in the process of neuropathology.Excessive choline treatment for Tg mice was used to investigate the role of abnormal choline metabolism on the cognitive functions.Our results showed that gut dysbiosis,neuroinflammation response,Ab deposition,tau hyperphosphorylation,TMAO overproduction and cyclin-dependent kinase 5(CDK5)/transcription 3(STAT3)activation occurred in Tg mice age-dependently.Disordered microbiota of aged Tg mice accelerated AD pathology in young Tg mice,with the activation of CDK5/STAT3 signaling in the brains.On the contrary,faecal microbiota transplantation from WT mice alleviated the cognitive deficits,attenuated neuroinflammation,Ab deposition,tau hyperphosphorylation,TMAO overproduction and suppressed CDK5/STAT3 pathway activation in Tg mice.Moreover,excessive choline treatment was also shown to aggravate the cognitive deficits,Ab deposition,neuroinflammation and CDK5/STAT3 pathway activation.These findings provide a novel insight into the interaction between gut dysbiosis and AD progression,clarifying the important roles of gut microbiota-derived substances such as TMAO in AD neuropathology.

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Effects of lead exposure on histological structure and antioxidant capacity in the cerebellum of 30-day-old mice

The current study sought to observe the effects of lead on histological structure and antioxidant capacity in 30-day-old mice.Spectrophotometry was used to detect the activities of superoxide dismutase,catalase,alkaline phosphatase,acid phosphatase and the malondialdehyde content.The results revealed that Purkinje cells in the lead-exposed group exhibited obvious pyknosis,atrophy and a decrease in overall number.Granular cells exhibited a disorderly arrangement,and were reduced in number.Administration of lead decreased the activities of superoxide dismutase,catalase,alkaline phosphatase and acid phosphatase,while malondialdehyde content increased.Two-way analysis of variance indicated that dose contributed more to lead-induced cerebellum damage than treatment time.The present study demonstrated that lead exerted strong effects on histological structure and inhibited antioxidant capacity of the cerebellum in 30-day-old mice.

Exosomes as mediators of neuron-glia communication in neuroinflammation

In recent years,a type of extracellular vesicles named exosomes has emerged that play an important role in intercellular communication under physiological and pathological conditions.These nanovesicles (30–150 nm) contain proteins,RNAs and lipids,and their internalization by bystander cells could alter their normal functions.This review focuses on recent knowledge about exosomes as messengers of neuron-glia communication and their participation in the physiological and pathological functions in the central nervous system.Special emphasis is placed on the role of exosomes under toxic or pathological stimuli within the brain,in which the glial exosomes containing inflammatory molecules are able to communicate with neurons and contribute to the pathogenesis of neuroinflammation and neurodegenerative disorders.Given the small size and characteristics of exosomes,they can cross the blood-brain barrier and be used as biomarkers and diagnosis for brain disorders and neuropathologies.Finally,although the application potential of exosome is still limited,current studies indicate that exosomes represent a promising strategy to gain pathogenic information to identify therapeutically targets and biomarkers for neurological disorders and neuroinflammation.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease

The most common age-related neurodegenerative disease is Alzheimer's disease(AD) characterized by aggregated amyloid-β(Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles,together with loss of cholinergic neurons,synaptic alterations,and chronic inflammation within the brain.These lead to progressive impairment of cognitive function.There is evidence of innate immune activation in AD with microgliosis.Classically-activated microglia(M1 state) secrete inflammatory and neurotoxic mediators,and peripheral immune cells are recruited to inflammation sites in the brain.The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects.Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials.Treatment with immunomodulatory/anti-inflammatory agents early in the disease process,while not preventive,is able to inhibit the inflammatory consequences of both Aβ and tau aggregation.The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD.The majority of the animal studies reviewed had used transgenic models of early-onset AD.More effort needs to be given to creat models of late-onset AD.The effects of a combinational therapy involving two or more of the tested pharmaceutical agents,or one of these agents given in conjunction with one of the cell-based therapies,in an aged animal model of AD would warrant investigation.

Comparison Study on Clinical and Neuropathological Characteristics of Hamsters Inoculated With Scrapie Strain 263K in Different Challenging Pathways

Objective To understand the infectious characteristics of a hamster-adapted scrapie strain 263K with five different routes of infection including intracerebral (i.e.), intraperitoneal (i.p.), intragastrical (i.g.), intracardiac and intramuscular (i.m.) approaches. Methods Hamsters were infected with crude- or fine-prepared brain extracts. The neuropathological changes, PrPSc deposits, and patterns of PK-resistant PrP were analyzed by HE stain, immunohistochemistry (IHC) assay and Western blot. Reactive gliosis and neuron loss were evaluated by glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE) specific IHC. Results The animals inoculated in i.m. and Lp. ways with crude PrPSc extracts showed clinical signs at the average incubation of 69.212.8 and 65.5±3.9 days. Inoculation in i.c. and intracardiac ways with fine PrPSc extracts (0.00035 g) caused similar, but relative long incubation of around 90 days. Only one out of eight hamsters challenged in i.g way with low dosage (0.01 g) became ill after a much longer incubation (185 d), while all animals (4/4) with high dosage (0.04 g) developed clinical signs 105 days postinfection. The most remarkable spongiform degeneration and PrPSc deposits were found in brain stem among the five challenge groups generally. The number of GFAP-positive astrocytes increased distinctly in brain stems in all infection groups, while the number of NSE-positive cells decreased significantly in cerebrum, except i.c. group. The patterns of PK-resistant PrP in brains were basically identical among the five infection routes. Conclusion Typical TSE could be induced in hamsters by inoculating strain 263K in the five infection ways. The incubation periods in bioassays depend on infective dosage, administrating pathway and preparation of PrPSc. The neuropathological changes and PrPSc deposits seem to be related with regions and inoculating pathways.

7.0T nuclear magnetic resonance evaluation of the amyloid beta(1–40) animal model of Alzheimer's disease: comparison of cytology verification

3.0T magnetic resonance spectroscopic imaging brain function in Alzheimer＇s disease. However, is a commonly used method in the research ot the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer＇s disease remains unclear. In this study, 7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer＇s disease rats, the N-acetylaspartate wave crest was reduced, and the creatine and choline wave crest was elevated. This finding was further supported by hematoxylin-eosin staining, which showed a loss of hippocampal neurons and more glial cells. Moreover, electron microscopy showed neuronal shrinkage and mitochondrial rupture, and scanning electron microscopy revealed small size hippocampal synaptic vesicles, incomplete synaptic structure, and reduced number. Overall, the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer＇s disease rats in vivo, allowing the possibility for assessing the success rate and grading of the amyloid beta （1-40） animal model of Alzheimer＇s disease.

Ototoxic effects of mefloquine in cochlear organotypic cultures

Mefloquine is a widely used anti-malarial drug. Some clinical reports suggest that mefloquine may be ototoxic and neurotoxic, but there is little scientific evidence from which to draw any firm conclusion. To evaluate the ototoxic and neurotoxic potential of mefloquine, we treated cochlear organotypic cultures and spiral ganglion cultures with various concentrations of mefloquine. Mefloquine caused a dose-dependent loss of cochlear hair cells at doses exceeding 0.01 mM. Hair cell loss progressed from base to apex and from outer to inner hair cells with increasing dose. Spiral ganglion neurons and auditory nerve fibers were also rapidly destroyed by mefloquine in a dose-dependent manner. To investigate the mechanisms underlying mefloquine-induced cell death, cochlear cultures were stained with TO-Pro-3 to identify morphological changes in the nucleus, and with carboxyfluorescein FAM-labeled caspase inhibitor 8, 9 or 3 to determine caspase-mediated cell death. TO-Pro-3-labeled nuclei in hair cells, spiral ganglion neurons and supporting cells were shrunken or fragmented, morphological features characteristic of cells undergoing apoptosis. Both initiator caspase 8 (membrane damage) and caspase 9 (mitochondrial damage), along with executioner caspase 3, were heavily expressed in cochlear hair cells and spiral ganglions after mefloquine treatment. These three caspases were also expressed in support cells, although labeling was less widespread and less intense. These results indicate that mefloquine damages both the sensory and neural elements in the postnatal rat cochlea by initially activating cell death signaling pathways on the cell membrane and in mitochondria.

Axonal damage in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in a C57BL/6 mouse model may be not secondary to inflammatory demyelination

The present study established a chronic experimental autoimmune encephalomyelitis model in C57BL/6 mice induced by myelin oligodendrocyte glycoprotein peptides and complete Freund＇s adjuvant. Onset latency was 12 days, with an incidence rate of 100%. Neuropathological characteristics included perivascular inflammatory cell infiltration, demyelination, neuronal degeneration, and axonal damage within cerebral and myelic white matter. Electron microscopy revealed swollen mitochondria, complete organ disappearance, and fused or broken myelin sheath structure, which were accompanied by myelin sheath reconstruction. Moreover, axonal damage was not consistent with demyelination distribution, and severity of axonal damage did not correlate with demyelination. Results suggested that axonal damage in an experimental autoimmune encephalomyelitis model is not secondary to inflammatory demyelination.

The subgenual cingulate gyrus exhibits lower rates of bifurcation in schizophrenia than in controls, bipolar disorder and depression

The subgenual cingulate cortex has been found to be different in structure and function in mood and affective disorders compared to healthy individuals. Imaging studies have shown a decrease in function of the subgenual region in bipolar disorder and depression, with overall glial number shown to be decreased in these disorders. Decreases in subgenual grey matter in SZ have been observed also. In this neuropathological study upon formalin-fixed coronal brain sections we describe the morphological finding of de- creased frequency of subgenual cingulate crown bifurcation (p = 0.02) as compared to control, bipolar and depression cases. This suggests that the cingulate cortex in schizophrenia may be morphologically distinct in utero formation, potentially enabling an early identification of high-risk individuals.

Neurological and behavioral manifestations of cerebral malaria:An update

Neglected tropical diseases are a group of tropical diseases endemic in poor countries even though medical treatment and cures are available. They are considered a global health problem due to the severity of the physiological changes they induce in their hosts. Malaria is a disease caused by Plasmodium sp. that in its cerebral form may lead to acute or long-term neurological deficits, even with effective antimalarial therapy, causing vascular obstruction, reduced cerebral blood flow and many other changes. However, Plasmodium falciparum infection can also develop into a cerebral malaria(CM) disease that can produce neurological damage. This review will discuss the mechanisms involved in the neuropathology caused by CM, focusing on alterations in cognitive, behavior and neurological functions in human and experimental models.

脑震荡及其法医学鉴定的讨论(附6分析)

作者在法医学尸体检验中曾遇到不同类型的脑震荡案例,现介绍6例,供读者分析参考。例1:王某,男,43岁。某年3月2日晚饭后,在通铺木板床上表演腾空翻跳,因失误头部着床跌倒在地,人事不省时隔20分钟左右死亡。

Rapid genetic screening of Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies patients

We used the allele-specific PCR-double digestion method on peripheral myelin protein 22 （PMP22） to determine duplication and deletion mutations in the proband and family members of one family with Charcot-Marie-Tooth disease type 1 and one family with hereditary neuropathy with liability to pressure palsies. The proband and one subclinical family member from the Charcot-Marie-Tooth disease type 1 family had a PMP22 gene duplication; one patient from the hereditary neuropathy with liability to pressure palsies family had a PMP22 gene deletion. Electron microscopic analysis of ultrathin sections of the superficial peroneal nerve from the two probands demonstrated demyelination and myelin sheath hyperplasia, as well as an ＇onion-like＇ structure in the Charcot-Marie-Tooth disease type 1A patient. We observed an irregular thickened myelin sheath and ＇mouse-nibbled＇-Iike changes in the patient with hereditary neuropathy with liability to pressure palsies. In the Charcot-Marie-Tooth disease type 1A patient, nerve electrophysiological examination revealed moderate-to-severe reductions in the motor and sensory conduction velocities of the bilateral median nerve, ulnar nerve, tibial nerve, and sural nerve. Moreover, the compound muscle action potential amplitude was decreased. In the patient with hereditary neuropathy with liability to pressure palsies, the nerve conduction velocity of the bilateral tibial nerve and sural nerve was moderately reduced, and the nerve conduction velocity of the median nerve and ulnar nerve of both upper extremities was slightly reduced.

Effects of Methadone Exposure during Development on Avian Brain and Blood Cells

Maintenance with methadone is standard treatment for opioid-addicted patients, including pregnant women. Cellular effects of methadone exposure during development are investigated by using an avian model, which is free of confounding maternal variables. In the first study, which explored dose by duration interactions, methadone was administered at one of two doses (0.458 mg/kg or 1.75 mg/kg) for one of three durations of exposure: late in development (Incubation Days 12 to 19), middle to late (Days 9 to 19), or early to late (Days 5 to 19). In the second study, 1.00 mg/kg of methadone was administered from days 8 to 18 and compared with controls (0.00 mg/kg). Brain tissue and blood samples were harvested for all dose conditions from the two studies. Increased methadone exposure was associated with subependymal anomalies, subependymal hemorrhaging, edema, monocytic infiltration, an increase in disintegrating red blood cells, an increase in white blood cells, and a decrease in neurons. Significant differences in variance for cell counts by condition were observed. Exposed specimens had significantly more thrombocytes (t = - 2.66, p < 0.05). The anomalies suggest that methadone exposure may be harmful to develop organisms at the cellular level.

Mavridis' atrophy in Parkinson's disease-five years later: Future perspectives

Mavridis' atrophy(MA) is called the human nucleus accumbens(NA) atrophy in Parkinson's disease(PD).MA begins in early-stage PD patients and is correlated with psychiatric symptoms that occur in PD, mainly apathy and impulsive behavior. It is also associated with cognitive PD symptoms. Purpose of this editorial was to discuss the future perspectives of MA as apathological and imaging finding. MA is obviously part of the degeneration of the dopaminergic nigrostriatal system that occurs in PD and this also explains the fact that MA precedes clinical phenotype. But does the human NA follow the same pattern of degeneration? It would be quite interesting to have a post-mortem pathological study focused on the NA of parkinsonic individuals. Further questions that remain to be answered are whether all parkinsonics suffer MA and whether this phenomenon is also associated with motor PD symptoms. MA as an imaging finding could be a risk factor for the expression and/or severity of specific PD symptoms. It has therefore to be tested whether the presence of MA is related, for example, with the expression and/or severity of motor PD symptoms and whether the severity of MA affects the severity of specific psychiatric symptoms(apathy, compulsive behavior) of parkinsonic individuals. Such clinical studies, that could provide answers to these vital questions, can be easily preformed given the high frequency of PD in modern populations. Future research efforts are mandatory to enrich our knowledge of MA, namely its underlying mechanisms, its pathological features and its clinical consequences.