Degeneration In Cortex Research Articles

Naringenin mitigates nanoparticulate-aluminium induced neuronal degeneration in brain cortex and hippocampus through downregulation of oxidative stress and neuroinflammation

Alumunium usage and toxicity has been a global concern especially an increased use of nanoparticulated aluminum (Al-NPs) products from the environment and the workplace. Al degrades in to nanoparticulate form in the environment due to the routine process of bioremediation in human body. Al-NPs toxicity plays key role in the pathophysiology of neurodegeneration which is characterised by the development of neurofibrillary tangles and neuritic plaques which correlates to the Alzheimer's disease. This study evaluated the Al-NPs induced neurodegeneration and causative behavioral alterations due to oxidative stress, inflammation, DNA damage, β-amyloid aggregation, and histopathological changes in mice. Furthermore, the preventive effect of naringenin (NAR) as a potent neuroprotective flavonoid against Al-NPs induced neurodegeneration was assessed. Al-NPs were synthesized and examined using FTIR, XRD, TEM, and particle size analyzer. Mice were orally administered with Al-NPs (6 mg/kg b.w.) followed by NAR treatment (10 mg/kg b.w. per day) for 66 days. The spatial working memory was determined by novel object recognition, T-maze, Y-maze, and Morris Water Maze tests. We measured nitric oxide, advanced oxidation of protein products, protein carbonylation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidised glutathione, and acetylcholine esterase, as well as cytokines analysis, immunohistochemistry, and DNA damage. Al-NPs significantly reduced the learning memory power, increased oxidative stress, reduced antioxidant enzymatic activity, increased DNA damage, altered the levels of cytokines, and increased β-amyloid aggregation in the cortex and hippocampus regions of the mice brain. These neurobehavioral impairments, neuronal oxidative stress, and histopathological alterations were significantly attenuated by NAR supplementation. In conclusion, Al-NPs may be potent neurotoxic upon exposure and that NAR could serve as a potential preventive measure in the treatment and management of neuronal degeneration.

Not a benign motor neuron disease: longitudinal imaging captures relentless motor connectome disintegration in primary lateral sclerosis.

Primary lateral sclerosis (PLS) is a progressive upper motor neuron disorder associated with considerable clinical disability. Symptoms are typically exclusively linked to primary motor cortex degeneration and the contribution of pre-motor, supplementary motor, cortico-medullary and inter-hemispheric connectivity alterations are less well characterized. In a single-centre, prospective, longitudinal neuroimaging study 41 patients with PLS were investigated. Patients underwent standardized neuroimaging, genetic profiling with whole exome sequencing, and comprehensive clinical assessments including upper motor neuron scores, tapping rates, mirror movements, spasticity assessment, cognitive screening and evaluation for pseudobulbar affect. Longitudinal neuroimaging data from 108 healthy controls were used for image interpretation. A standardized imaging protocol was implemented including 3D T1-weighted structural, diffusion tensor imaging and resting-state functional magnetic resonance imaging. Following somatotopic segmentation, cortical thickness analyses, probabilistic tractography, blood oxygenation level dependent signal analyses and brainstem volumetry were conducted to evaluate cortical, brainstem, cortico-medullary and inter-hemispheric connectivity alterations both cross-sectionally and longitudinally. Our data confirm progressive primary motor cortex degeneration, considerable supplementary motor and pre-motor area involvement, progressive brainstem atrophy, cortico-medullary and inter-hemispheric disconnection, and close associations between clinical upper motor neuron scores and somatotopic connectivity indices in PLS. Primary lateral sclerosis is associated with relentlessly progressive motor connectome degeneration. Clinical disability in PLS is likely to stem from a combination of intra- and inter-hemispheric connectivity decline and primary, pre- and supplementary motor cortex degeneration. Simple 'bedside' clinical tools, such as tapping rates, are excellent proxies of the integrity of the relevant fibres of the contralateral corticospinal tract.

Evaluation of anti-Alzheimer activity of Echinacea purpurea extracts in aluminum chloride-induced neurotoxicity in rat model

Alzheimer's disease (AD) is one of the neurodegenerative illnesses that impair individual life & increase the demand for caregivers with no available curative medication right now. Therefore, there is a growing concern about employing herbal medicine to limit AD progression & improve patients' life quality, thus potentiating its add-on therapy. In addition, herbs are cost-effective & accessible with nearly no side effects. In the same vein, our study aimed to investigate the potency of Echinacea purpurea (EP) flower extracts to ameliorate the neurodegenerative effect of Aluminum chloride (AlCl3) in a rat model. Moreover, mechanistic studies, including impact on the cholinesterase activity, redox status, inflammatory mediators, behavior performance, glucose level & histopathology, were carried on. Our results showed that 250 mg/kg of Aqueous (AQ) & Alcoholic (AL) extracts of EP inhibited cholinesterase, restored oxidative balance, down-regulated IL-6 & TNF-α cytokines & improved behavior performance in vivo that was reflected in the brain picture by decreasing neuronal degeneration & amyloid plaques in cerebral cortex & hippocampus. The potency of both extracts was compared to reference drugs & AlCl3 positive control group. The AQ extract showed greater potency against COX-1, COX-2 & α-amylase in vitro, while the AL extract was more potent against cholinesterase in vitro, inflammatory cytokines, behavior & pathological improvement in vivo. Conclusively EP overcame AlCl3-induced neurobehavioral toxicity in the rat model via different pathways, which support its regular administration to postpone progressive neural damage in AD patients.

NADPH oxidase and endoplasmic reticulum stress is associated with neuronal degeneration in orbitofrontal cortex of individuals with alcohol use disorder.

Many disorders of the central nervous system (CNS), including alcohol use disorder (AUD), are associated with induction of proinflammatory neuroimmune signalling and neurodegeneration. In previous studies, we found increased expression of Toll-like receptors (TLRs), activated NF-κB p65 (RELA), and other proinflammatory signalling molecules. Proinflammatory NADPH oxidases generate reactive oxygen species, which are linked to neurodegeneration. We tested the hypothesis that AUD increased RELA activation increases NADPH oxidase-oxidative stress and endoplasmic reticulum (ER) stress cell death cascades in association with neuronal cell death in the human orbitofrontal cortex (OFC). In the AUD OFC, we report mRNA induction of several NADPH oxidases, the dual oxidase DUOX2, and the oxidative stress lipid peroxidation marker 4-HNE and the DNA oxidation marker 8-OHdG that correlate with RELA, a marker of proinflammatory NF-κB activation. This was accompanied by increased expression of the ER stress-associated regulator protein glucose-regulated protein 78 (GRP78), transmembrane sensors activating transcription factor 6 (ATF6), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and inositol-requiring kinase/endonuclease 1 (pIRE1), and the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Expression of NADPH oxidase-oxidative stress markers correlate with ER stress-associated molecules. Induction of oxidative stress and ER stress signalling pathways correlate with expression of cell death-associated caspases and neuronal cell loss. These data support the hypothesis that proinflammatory RELA-mediated induction of NADPH oxidase-oxidative stress and ER stress-associated signalling cascades is associated with neuronal cell death in the post-mortem human OFC of individuals with AUD.

Peroral Exposure to Cannabis Sativa Ethanol Extract Caused Neuronal Degeneration and Astrogliosis in Wistar Rats' Prefrontal Cortex.

Despite widespread concerns about its possible side effects, notably on the prefrontal cortex (PFC), which mediates cognitive processes, the use of Cannabis sativa as a medicinal and recreational drug is expanding exponentially. This study evaluated possible behavioral alterations, neurotransmitter levels, histological, and immunohistochemical changes in the PFC of Wistar rats exposed to Cannabis sativa. To evaluate the effect of graded doses of Cannabis sativa on the PFC using behavioural, histological, and immunohistochemical approaches. Twenty-eight juvenile male Wistar rats weighing between 70 g and 100 g were procured and assigned into groups A-D (n = 7 each). Group A served as control which received distilled water only as a placebo; rats in groups B, C, and D which were the treatment groups were orally exposed to graded doses of Cannabis sativa (10 mg/kg, 50 mg/kg, and 100 mg/kg, respectively). Rats in all experimental groups were exposed to Cannabis sativa for 21 days, followed by behavioral tests using the open field test for locomotor, anxiety, and exploratory activities, while the Y-maze test was for spatial memory assessment. Rats for biochemical analysis were cervically dislocated and rats for tissue processing were intracardially perfused following neurobehavioral tests. Sequel to sacrifice, brain tissues were excised and prefrontal cortices were obtained for the neurotransmitter (glutamate, acetylcholine, and dopamine) and enzymatic assay (Cytochrome C oxidase (CcO) and Glucose 6- Phosphate Dehydrogenase-G-6-PDH). Brain tissues were fixed in 10% Neutral Buffered Formalin (NBF) for histological demonstration of the PFC cytoarchitecture using H&E and glial fibrillary acidic protein (GFAP) for astrocyte evaluation. Glutamate and dopamine levels were significantly increased (F = 24.44, P = .0132) in groups D, and B, C, and D, respectively, compared to control; likewise, the activities of CcO and G-6-PDH were also significantly elevated (F = 96.28, P = .0001) (F = 167.5, P = .0001) in groups C and D compared to the control. Cannabis sativa impaired locomotor activity and spatial memory in B and D and D, respectively. All Cannabis sativa exposed groups demonstrated evidence of neurodegeneration in the exposed groups; GFAP immunoexpression was evident in all groups with a marked increase in group D. Cannabis sativa altered neurotransmitter levels, energy metabolism, locomotor, and exploratory activity, and spatial working memory, with neuronal degeneration as well as reactive astrogliosis in the PFC.

Iron Chelation Remits Memory Deficits Caused by the High-Fat Diet in a Mouse Model of Alzheimer's Disease.

Obesity is a worldwide health problem that has been implicated in many diseases, including Alzheimer's disease (AD). AD is one of the most common neurodegenerative disorders and is characterized by two pathologies, including extracellular senior plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) consisting of abnormally hyperphosphorylated tau. According to current research, a high-fat diet (HFD) could exacerbate Aβ accumulation, oxidative damage, and cognitive defects in AD mice. However, the accurate role of HFD in the pathogenesis of AD is far more unclear. To explore the accurate role of HFD in the pathogenesis of AD. Open Field, Barns Maze, Elevated zero-maze, Contextual fear condition, Tail suspension test, western blotting, immunofluorescence, Fluoro-Jade C Labeling, Perls' Prussian blue staining, and ELISA were used. HFD caused nonheme iron overload in the brains of APPswe/PS1dE9 (APP/PS1) mice. Furthermore, the administration of M30 (0.5 mg/kg) for iron chelation once every 2 days per os (p.o.) for 1 month remitted memory deficits caused by HFD in APP/PS1 mice. Notably, a variety of hematological parameters in whole blood had no difference after iron chelation. In addition, iron chelation effectively reduced synaptic impairment in hippocampus and neuronal degeneration in cortex in the HFD-fed APP/PS1 mice. Meanwhile, iron chelation decreased Aβ1-40 and Aβ1-42 level as well as neuroinflammation in HFD-fed APP/PS1 mice. These data enhance our understanding of how HFD aggravates AD pathology and cognitive impairments and might shed light on future preclinical studies.

Age-dependent effect of continuous 'artificial light at night' on circadian rhythm in male rats: neuroprotective role of melatonin.

Circadian disruption due to artificial light at night (ALAN) is an alarming threat to modern society. In the present study we evaluated the protective effect of melatonin on age dependent redox insults and neurochemical deficits induced by ALAN in the brain of chronodisrupted rat model. Young (3months) and old (22months) male Wistar rats were exposed to ALAN along with melatonin supplementation (10mgKg-1, oral) for 10days. Results demonstrated significant increment in the pro-oxidant biomarkers: reactive oxygen species, lipid hydroperoxidation, protein carbonyl, nitric oxide while suppression in the total thiol, ferric reducing antioxidant potential level, superoxide dismutase and catalase activities in the brain of ALAN exposed groups with higher amplitude in aged rats. Further these oxidative modifications were protected by subsequent administration of melatonin. Mitochondrial complexes (C-I to C-IV) activity was significantly altered in young and old ALAN exposed groups with melatonin showing protective effect. Histopathological analysis show dense cytosolic staining and neuronal degeneration in cerebral cortex and different hippocampus regions with greater extent in old ALAN rats effectively moderated by melatonin supplementation. RT-PCR data analysis revealed melatonin effectively downregulated neuroinflammatory (IL-6, TNF α) and neurodegenerative marker (Ngb) while upregulating the aging (Sirt 1) gene expression in both young and old melatonin supplemented ALAN exposed groups. Our results may help in understanding the degree of ALAN induced photo-oxidative damage in neuronal redox homeostasis during aging. We also show that melatonin supplementation might provide a basis for amelioration of oxidative disturbances to improve circadian entrainment in aged populations.

Benefits of betanin in rotenone-induced Parkinson mice.

The present study aimed to investigate betanin's neuroprotective effect in mice with rotenone-induced Parkinson-like motor dysfunction and neurodegeneration. Forty male ICR mice were divided into 4 groups: Sham-veh, Rot-veh, Rot-Bet100 and Rot-Bet200. Rotenone at 2.5mg/kg/48h was subcutaneous injected in Rot groups, and betanin at 100 and 200mg/kg/48h were given alternately with the rotenone injections in Bet groups for 6weeks. Motor dysfunctions were evaluated weekly using hanging wire and rotarod tests. Brain oxidative status including malondialdehyde, reduced glutathione, catalase, superoxide dismutase, with neuronal degeneration in the motor cortex, striatum and substantia nigra par compacta were evaluated. The immunohistochemical densities of tyrosine hydroxylase in striatum and in substantia nigra par compacta were also measured. We found that rotenone significantly decreased the time to fall in a hanging wire test after the 4th week and after the rotarod test at the 6th week (p < 0.05). The percentage of neuronal degeneration in substantia nigra par compacta, striatum and motor cortex significantly increased (p < 0.05), and the tyrosine hydroxylase density in substantia nigra par compacta and in striatum significantly decreased (p < 0.05). Betanin at 100 and 200mg/kg significantly prevented substantia nigra par compacta, striatum and motor cortex neuronal degeneration (p < 0.05) and maintained tyrosine hydroxylase density in substantia nigra par compacta and in striatum (p < 0.05). These findings appeared concurrently with improved effects on the time to fall in hanging wire and rotarod tests (p < 0.05). Treatment with betanin significantly prevented increased malondialdehyde levels and boosted reduced glutathione, catalase and superoxide dismutase activities (p < 0.05). Betanin exhibits neuroprotective effects against rotenone-induced Parkinson in mice regarding both motor dysfunction and neurodegeneration. Betanin's neurohealth benefit relates to its powerful antioxidative property. Therefore, betanin use in neurodegenerative disease is interesting to study.

Use of methylphenidate in alzheimer’s dementia: Effect on apathy

IntroductionAlzheimer’s Disease (AD) is associated with neuropsychiatric symptoms such as agitation depression and apathy. It has been proposed that the pathophysiology of apathy, that is defined as quantitative reduction in goal-directed activity compared with previous functioning, in AD is associated with degeneration of prefrontal cortex and dysfunction of dopamine and norepinephrine neurons in the brain. Methylphenidate (MPH) is a dopamine and norepinephrine reuptake inhibitor and its action increase the availability of these neurotransmitters in the extracellular space of striatum and prefrontal cortex. Over the past decade there has been an effort to study the benefit of the use of MPH for treatment of apathy in patients with Alzheimer’s dementia.ObjectivesStudy the benefit of methylphenidate in the treatment of apathy in AD.MethodsBasic literature review collecting data from PubMed (2010-2020) using the words “Methylphenidate”, “Apathy”, “Alzheimer”, “Dementia”.ResultsClinical trials using 10 to 20mg of MPH per day, for 6 weeks, demonstrated a mitigation in apathy symptoms in one third of patients, with good tolerability. Another clinical trial using the same dosage, for 12 weeks, led to improvement in cognition, functional status, depression and caregiver burden.ConclusionsNew clinical trials with larger groups of patients over a longer period are needed to consolidate the existing results. Although there are still many questions concerning the usefulness of methylphenidate in this population that need to be answered, methylphenidate might be an option to deal with one of the most prevalent neuropsychiatric symptoms, apathy, in some AD patients.

Prediction of cognitive function based on structural MRI images using a 3D convolutional neural net among cognitively normal older adults

<h3>Introduction</h3> It is projected that 30 years from now, more than 12 million US adults may be affected by neurodegenerative diseases such as Alzheimer's Disease. With no cure on the market and the looming societal pressure to care for the burgeoning numbers of elderly patients, the goal of modern medicine should be to identify patients at risk for dementia and intervene early on. Machine learning algorithms have been successful at classifying which patients have Alzheimer's Disease and which patients do not based off an MRI and/or PET image. Although neurodegenerative diseases are quite prevalent in elderly individuals, no machine learning algorithm has been developed to predict which healthy adults are at heightened risk for developing neurodegenerative diseases. Here, we take the first step towards this goal by predicting an individual's current cognitive function based off of a singular MRI. We drew inspiration from 3D convolutional neural nets (CNNs) to predict a cognitive test score at present based on a raw MRI image among cognitively normal older adults. <h3>Methods</h3> We analyzed data from 159 community dwelling cognitively normal individuals (mean age = 76.3 yo ± 6.5, 34% male). A neural net was designed to include four convolutional layers that used 3x3x3 filters. Each layer generated eight, 16, 32, and 64 feature maps respectively and each layer was normalized and followed by a max pooling layer. The convolutional layers were followed by two fully connected layers with 128 and 64 neurons respectively and the final output involved one output neuron that used a rectilinear activation function. Mean squared error loss was used to adjust the weights of the neural net, and the learning rate was set to 0.001. The inputs to the CNN were 159 skull stripped MPRAGE MR-T1 weighted images registered to MNI space and randomly rotated and translated (probability = 0.3). 20% of the data was held out for validation. The outcome variables were composite cognitive score and subdomain scores (i.e., memory-retrieval, memory-learning, language, visuospatial, and executive attention) which were derived from 21 different neuropsychological tests grouped according to the literature to reflect cognitive function across five different cognitive domains. The cognitive scores computed amongst all five subdomains were normally distributed. A cross-validated linear regression to predict cognitive function from age served as a comparative model since it is a clinically popular model. <h3>Results</h3> The 3D CNN demonstrated that when age was a statistically significant predictor of cognitive subdomain score or composite cognitive score (p < 0.001), the ratio of the mean squared error loss of a simple linear regression to the mean squared error loss from the CNN ranged from 1.10 to 1.47. This was true for the composite cognitive score as well as the executive attention and visuospatial subdomain scores. However, when age was not a statistically significant predictor of cognition, as was the case for memory-learning, memory-retrieval and language subdomain scores, the range of the ratio increased to 1.59 to 2.23. The most relevant areas of the brain that predicted cognition were cortical areas of the brain that are most sensitive to neurodegeneration with age including the cerebellum, frontal, and temporal lobes. <h3>Conclusions</h3> When age is not a statistically significant correlate of cognitive function, machine learning is at least 1.5 times better than a linear regression model at predicting cognitive function based on a single MRI. Furthermore, the areas of the brain that are most significant in predicting cognition in cognitively normal older adults provide both validation of our methodology as well as new insights. The 3D CNN gained the most amount of insight from the mid frontal lobe and inferior temporal lobe, brain regions known to be susceptible to neurodegeneration associated with aging. The 3D CNN, without any such foresight, replicated what we know to be already true. Additionally, the 3D CNN gained considerable insight from the cerebellum as well. Perhaps the significance was given to the frontal portion of the cerebellum as it could foreshadow future frontal cortex degeneration. Overall, the 3D CNN developed here was successful at predicting cognition off a singular MRI, outperforms current linear regression models, affirms the current state of knowledge regarding brain regions correlated with cognition, and provides novel insight into which brain regions are predictive of cognitive function. The model provides hope that it can be used as a tool to predict future cognitive decline in an elderly individual. The ability to predict future cognition would allow clinicians to identify those patients who are at considerable risk for abnormally steep changes in cognitive function and provide preemptive care to individuals more at risk for neurodegenerative diseases. <h3>Funding</h3> University of Pittsburgh School of Medicine Physician Scientist Training Program

Dioraleze Drug-induced Kidney Injury In Rats

The present study was designed to find out the effects of Dioraleze administered orally on the kidney.&#x0D; In this study the experiment was designed using twenty Rats from both sexes and randomly distributed into three main groups as following:&#x0D; Group 1 (Control): Distilled Water was administered orally on a daily basis for three weeks.&#x0D; Group 2 (Treatment): 1mg/kg body weight Dioraleze was administered orally on a daily basis for three weeks.&#x0D; Group 3 (Overdose): orally given 2.5mg/kg body weight Dioraleze daily for three weeks.&#x0D; At the end of the experimental period Rats were taken out and dissected for histological examination and processing. Kidney tissue was examined for any abnormalities.&#x0D; Drug-induced kidney disease is usually a result of a drug or metabolites that could affect the cell and tissue biochemistry directly or result in an immune response which was found in this study as the occurrence of several vascular sacs directly attached to the liver in all rats present in group 2 and 3. The sac ranged in size from 0.5 cm-1 cm compared to group 1 which showed the lack of any sacs.&#x0D; Kidney in both therapeutic and Overdose group illustrated many abnormalities after treatment period when compared to Control. Some of these alterations in tissue and organ such as renal cortex degeneration, atrophy of proximal convoluted tubule that led to necrosis, blood congestion and hypertrophy was also present in the Glomerulus of treated Rats.&#x0D; Renal medulla, however illustrated atrophy of the proximal convoluted tubules, degeneration of renal tubule epithelial cells and ultimately their shrinkage leading to a small lumen in addition to the pyknosis of nuclei.&#x0D; Kidney examination revealed Dioraleze’s significant impact on the renal cortex and medulla in addition to its effect of other parts of kidney tissue. Thus, it was concluded that Dioraleze caused kidney abnormalities that may lead to kidney dysfunction in the body and may also have great impact on other visceral organs if not taken as per dose.

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord.

Understanding the cellular and molecular basis of selective vulnerability has been challenging, especially for motor neuron diseases. Developing drugs that improve the health of neurons that display selective vulnerability relies on in vivo cell-based models and quantitative readout measures that translate to patient outcome. We initially developed and characterized UCHL1-eGFP mice, in which motor neurons are labeled with eGFP that is stable and long-lasting. By crossing UCHL1-eGFP to amyotrophic lateral sclerosis (ALS) disease models, we generated ALS mouse models with fluorescently labeled motor neurons. Their examination over time began to reveal the cellular basis of selective vulnerability even within the related motor neuron pools. Accumulation of misfolded SOD1 protein both in the corticospinal and spinal motor neurons over time correlated with the timing and extent of degeneration. This further proved simultaneous degeneration of both upper and lower motor neurons, and the requirement to consider both upper and lower motor neuron populations in drug discovery efforts. Demonstration of the direct correlation between misfolded SOD1 accumulation and motor neuron degeneration in both cortex and spinal cord is important for building cell-based assays in vivo. Our report sets the stage for shifting focus from mice to diseased neurons for drug discovery efforts, especially for motor neuron diseases.

Neurotoxicity of green- synthesized magnetic iron oxide nanoparticles in different brain areas of wistar rats

AimsThe aim of the present study was to evaluate the toxicity of magnetic iron oxide nanoparticles (MIONs) which were synthesized using carob leaf extract on various brain areas of Wistar rats. Main methodsCarob leaf synthesized-MIONs were characterized using different techniques: Dynamic Light Scattering (DLS), Transmission Electron Microscope (TEM), UV–vis spectrophotometer, Fourier Transform infrared (FTIR), X-Ray Diffraction (XRD) and Atomic Force Microscope (AFM). The toxicity of MIONs in vivo was evaluated by: monitoring rat’s body weight, measuring iron content in different brain areas, evaluating some oxidative stress parameters, estimating acetylcholinesterase (AChE) in addition to histopathological investigations. Key findingsThe present study demonstrated no body weight changes of MIONs- treated rats. According to the conditions of the present study, the hippocampus and striatum were the most affected areas and demonstrated neuronal degeneration due to MIONs exposure. MIONs treatment of Wistar rats, also affected the iron homeostasis in both striatum and midbrain by decreasing iron content in these areas. The least affected areas were thalamus and cerebellum. The histopathological examination of brain areas demonstrated moderate neuronal degeneration in hippocampus and striatum, mild neuronal degeneration in cortex and slight degeneration in hypothalamus and pons-medulla areas were detected. SignificanceThe results suggested that MIONs have a toxic impact on different brain areas and the effect varies according to the brain area.

Abstract 19: Ultra-Fast Cooling Induced by Total Liquid Ventilation Provides Neuroprotection Through a Delay in the Acute Systemic Inflammatory Response After Cardiac Arrest in Rabbits

Introduction: Ultra-fast cooling with total liquid ventilation (TLV) is potently protective in animal models of cardiac arrest. Hypothesis: Here, we hypothesized that this protection involves a mitigation of the acute phase of the inflammatory syndrome after cardiac arrest. Methods: Rabbits were anesthetized and submitted to 10 min of ventricular fibrillation. After resuscitation, animals underwent normothermic follow-up (Control, n=6) or ultra-fast cooling by TLV started after resuscitation (TLV, n=6). TLV was used for induction of cooling during 20 min and hypothermia was further maintained during 3 h using external techniques before rewarming. A third group was submitted to a Sham procedure (n=5). Survival and neurological dysfunction were assessed during 3 days. Results: TLV improved the clinical neurological recovery as compared to Control group after cardiac arrest. It was corroborated by histological examination showing an attenuation of neuronal degeneration in parasagittal cortex and hippocampus in TLV vs Control groups. After resuscitation, TLV delayed the elevation of interleukin-6 blood levels as compared to Control after cardiac arrest (e.g., 298±63 vs 991±471 pg/ml at 180 min after cardiac arrest in TLV vs Control, respectively). Blood cytometry analyses showed a massive recruitment of neutrophils and leukocytes (including T4, T8 and B-lymphocytes) in both groups. The early lymphocytosis was attenuated in TLV vs Control groups, despite not achieving statistical significance. Blood levels of high-mobility group box 1 increased rapidly and similarly in both groups after cardiac arrest. This suggests that TLV does not mitigate the early release of danger-associated molecular patterns after resuscitation, which is closely related to the immediate cell death after resuscitation. Altogether, these results show an attenuation of the early inflammatory response during hypothermia, suggesting a role of early but not delayed inflammation in the mechanism of ultra-fast cooling after cardiac arrest. Conclusion: Beneficial effect of hypothermic TLV could be explained by a delay in immune peripheral cells activation and cytokine release, rather than sustained inhibition of inflammation after cardiac arrest.

Effect of P-Hydroxycinnamic Acid in Mice Model of Cerebral Ischemia-Reperfusion Injury

Multiple pathomechanisms of cerebral ischemia reperfusion (I/R) injuries can be ameliorated by certain high-potential pharmaceutical substances. In the present study, we investigated the acute effect of p-hydroxycinnamic (pHCA) acid against cerebral I/R injury in mice. Thirty male ICR mice were divided into Sham, Control-I/R, and pHCA-I/R groups. The pHCA 100 mg/kg and the vehicle were given 30 min before I/R induction. Thirty-minute bilateral common carotid artery occlusion followed by 45-min reperfusion was performed on the Control-I/R and pHCA-I/R groups. Brains were collected for biochemical analysis, infarction and histological study of the cerebral cortex and corpus callosum (CC). The results showed that I/R induction significantly induced biochemical changes (p<0.05) along with the increase of brain infarction (p<0.05), percentage of degeneration in cerebral cortex (p<0.05) and decrease of CC white matter density (p<0.05). Pretreatment with pHCA significantly reduced MDA (p<0.05), brain infarction (p<0.05), cerebral cortex neuronal degeneration (p<0.05) and prevented the reduction of white matter density in the CC (p<0.05). The present study concluded that pretreatment with pHCA helps prevent cerebral I/R injury by amelioration of lipid peroxidation, white matter damage and neuronal degeneration.

Activation of the primary motor cortex using fully-implanted electrical sciatic nerve stimulation.

Functional degradation of the motor cortex usually results from brain injury, stroke, limb amputation, aging or other diseases. Currently, there are no ideal means of treatment, other than medication and sports rehabilitation. The present study investigated whether electrical stimulation of the sciatic nerve can activate the motor-related area of the brain. The study is based on a self-developed fully implantable nerve electrical stimulator and a self-developed multi-channel electroencephalogram (EEG) electrode array. The sciatic nerves of Sprague-Dawley rats (sorted into old and young groups) were stimulated by the electrical stimulator under anesthesia, and the EEG signal was recorded simultaneously. The relationship between sciatic nerve stimulation and brain activity was analyzed. The results showed that when the sciatic nerve was stimulated by the implanted electrical stimulator, motor-related channels were activated, causing contraction of the left leg. It was found that at the frequency band of 8–16 Hz, the EEG signal in the right motor area was higher than at other frequency bands. This phenomenon was identical in both young and old rats. The results indicated that electrical stimulation of the sciatic nerve can activate the motor region of the rat brain, and provided evidence that stimulation of the sciatic nerve could be a method of preventing motor cortex degeneration.

White Matter Microstructural Change Contributes to Worse Cognitive Function in Patients With Type 2 Diabetes.

Patients with type 2 diabetes mellitus (T2DM) have a considerably high risk of developing dementia, especially for those with mild cognitive impairment (MCI). The investigation of the microstructural change of white matter (WM) between T2DM with amnesic MCI (T2DM-aMCI) and T2DM with normal cognition (T2DM-NC) and their relationships to cognitive performances can help to understand the brain variations in T2DM-related amnesic cognitive impairment. In the current study, 36 T2DM-aMCI patients, 40 T2DM-NC patients, and 40 healthy control (HC) individuals underwent diffusion tensor image and T1-weighted MRI scans and comprehensive cognition assessments. All of these cognitive functions exhibited intergroup ranking differences in patients. The T2DM-NC patients and HC individuals did not reveal any significant differences in WM integrity. The T2DM-aMCI patients showed disrupted integrity in multiple WM tracts compared with HC and T2DM-NC. Specifically, the damaged WM integrity of the right inferior fronto-occipital fasciculus and the right inferior longitudinal fasciculus exhibited significant correlations with episodic memory and attention function impairment in T2DM patients. Furthermore, cognitive impairment-related WM microstructural damage was associated with the degeneration of cortex connected to the affected WM tract. These findings indicate that degeneration exists extensively in WM tracts in T2DM-aMCI, whereas no brain WM damage is evident in T2DM-NC.

Erythropoietin Reduces Neurodegeneration and Long-Term Memory Deficits Following Sevoflurane Exposure in Neonatal Rats.

Exposure to general anesthetics induces neural apoptosis and degeneration in the immature neonatal brain. Erythropoietin (EPO) has been shown to protect neonatal animals against hypoxic-ischemic injury and general anesthesia-induced developmental neurotoxicity. However, preventive strategy caused by EPO against neurotoxicity due to general anesthesia is still uncertain. This study examined the effects of EPO administration on brain cytology and cognitive function in adolescent rats exposed to 3% sevoflurane as neonates. Seven-day-old rats received intraperitoneal saline (EPO 0U group) or EPO (60, 120, or 600U) 30min before exposure to 3% sevoflurane with 21% oxygen for 4h. The rats only received 21% oxygen without EPO and sevoflurane as the sham group. The Morris water maze task was performed time-dependently among the groups, 3weeks post-anesthesia exposure. Escape latency and % quadrant in the EPO 600U group were significantly reduced and increased, respectively, compared with those in the EPO 0U group 6weeks post-exposure. In addition, freezing time in response to the conditioned stimulus and the number of NeuN-positive cells in the hippocampal CA1 region were significantly increased in the EPO 120 and 600U groups than in the EPO 0U group 6weeks after exposure. Moreover, the statistical parameter mapping of positive cell density was increased in the EPO-treated rats. These results support the observations that pretreatment with EPO reduced long-term cognitive deficits and neuronal degeneration in cortex and hippocampus induced by sevoflurane exposure with low oxygen concentration in neonatal rats.

Timing correlations between cerebellar interpositus neuronal firing and classically conditioned eyelid responses in wild-type and Lurcher mice

Classical eyeblink conditioning is an experimental model widely used for the study of the neuronal mechanisms underlying the acquisition of new motor and cognitive skills. There are two principal interpretations of the role of the cerebellum in the learning of eyelid conditioned responses (CRs). One considers that the cerebellum is the place where this learning is acquired and stored, while the second suggests that the cerebellum is mostly involved in the proper performance of acquired CRs, implying that there must be other brain areas involved in the learning process. We checked the timing of cerebellar interpositus nucleus (IPN) neurons’ firing rate with eyelid CRs in both wild-type (WT) and Lurcher (a model of cerebellar cortex degeneration) mice. We used delay and trace conditioning paradigms. WT mice presented a better execution for delay vs. trace conditioning and also for these two paradigms than did Lurcher mice. IPN neurons were activated during CRs following the activation of the orbicularis oculi muscle. Firing patterns of IPN neurons were altered in Lurcher mice. In conclusion, the cerebellum seems to be mostly related with the performance of conditioned responses, rather than with their acquisition.

Intermittent hypoxia improves behavioral and adrenal gland dysfunction induced by posttraumatic stress disorder in rats.

Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.