Degeneration Of Neuronal Cells Research Articles

Understanding the Mechanism of Ferroptosis in Neurodegenerative Diseases.

Neurodegenerative disorders are typified by the progressive degeneration and subsequent apoptosis of neuronal cells. They encompass a spectrum of conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), epilepsy, brian ischemia, brian injury, and neurodegeneration with brain iron accumulation (NBIA). Despite the considerable heterogeneity in their clinical presentation, pathophysiological underpinning and disease trajectory, a universal feature of these disorders is the functional deterioration of the nervous system concomitant with neuronal apoptosis. Ferroptosis is an iron (Fe)-dependent form of programmed cell death that has been implicated in the pathogenesis of these conditions. It is intricately associated with intracellular Fe metabolism and lipid homeostasis. The accumulation of Fe is observed in a variety of neurodegenerative diseases and has been linked to their etiology and progression, although its precise role in these pathologies has yet to be elucidated. This review aims to elucidate the characteristics and regulatory mechanisms of ferroptosis, its association with neurodegenerative diseases, and recent advances in ferroptosis-targeted therapeutic strategies. Ferroptosis may therefore be a critical area for future research into neurodegenerative diseases.

Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer's Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy.

Peroxisome proliferator-activated receptors (PPARs) may play an important role in the pathomechanism/pathogenesis of Alzheimer's disease (AD) and several other neurological/neuropsychiatric disorders. AD leads to progressive alterations in the redox state, ion homeostasis, lipids, and protein metabolism. Significant alterations in molecular processes and the functioning of several signaling pathways result in the degeneration and death of synapses and neuronal cells, leading to the most severe dementia. Peroxisome proliferator-activated receptor alpha (PPAR-α) is among the processes affected by AD; it regulates the transcription of genes related to the metabolism of cholesterol, fatty acids, other lipids and neurotransmission, mitochondria biogenesis, and function. PPAR-α is involved in the cholesterol transport to mitochondria, the substrate for neurosteroid biosynthesis. PPAR-α-coding enzymes, such as sulfotransferases, which are responsible for neurosteroid sulfation. The relation between PPAR-α and cholesterol/neurosteroids may have a significant impact on the course and progression of neurodegeneration/neuroprotection processes. Unfortunately, despite many years of intensive studies, the pathogenesis of AD is unknown and therapy for AD and other neurodegenerative diseases is symptomatic, presenting a significant goal and challenge today. This review presents recent achievements in therapeutic approaches for AD, which are targeting PPAR-α and its relation to cholesterol and neurosteroids in AD and neuropsychiatric disorders.

Neurotherapeutic Comparison of Aripiprazole and Ethanolic Extract of Fragaria Ananassa on Cerebrum and Amygdala of Methamphetamine Intoxicated Male Wistar Rats

The obvious need for other effective therapeutic medications for methamphetamine-induced cerebral and amygdala toxicity has warranted this research. _Fragaria ananassa, _extracted ethanolically. The current study looked at the neurotherapeutic effects of the ethanolic extract of _Fragaria ananassa _on the cerebrum and amygdala of methamphetamine-intoxicated Wistar rats. The rats were divided into 8 groups. Oxidative stress markers were analysed, neurobehavioural tests were carried out, and histological examination was done. SPSS version 20.0 was used to analyze the data, with a significance level of 0.05 considered significant. Group A was the control group, and B received 100mg/kg of meth. Group C received 200mg/kg of the ethanolic extract of strawberry. Groups D, E, and F received 100mg/kg of meth and 100mg/kg of the ethanolic extract of strawberry, and, finally, 100mg/kg of meth was treated with 200mg/kg of the ethanolic extract of strawberry and 10mg/kg of aripiprazole, respectively. The correlation between the initial weight and the final weight showed an obvious increase in the weight of the rats, especially in the control group (A) and the F and G groups. The histoarchitecture showed marked degeneration of neuronal cells in group B, which received methamphetamine alone, but knew further improvement in groups that were subsequently treated with the extract. The study further demonstrates that oxidative stress markers (SOD, MDA, CAT) were not significantly altered as long as the ethanolic extracts of strawberry were administered alongside the ingested methamphetamine, in line with other hypotheses.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus.

Recent investigations of COVID-19 have largely focused on the effects of this novel virus on the vital organs in order to efficiently assist individuals who have recovered from the disease. In the present study we used hippocampal tissue samples extracted from people who died after COVID-19. Utilizing histological techniques to analyze glial and neuronal cells we illuminated a massive degeneration of neuronal cells and changes in glial cells morphology in hippocampal samples. The results showed that in hippocampus of the studied brains there were morphological changes in pyramidal cells, an increase in apoptosis, a drop in neurogenesis, and change in spatial distribution of neurons in the pyramidal and granular layer. It was also demonstrated that COVID-19 alter the morphological characteristics and distribution of astrocyte and microglia cells. While the exact mechanism(s) by which the virus causes neuronal loss and morphology in the central nervous system (CNS) remains to be determined, it is necessary to monitor the effect of SARS-CoV-2 infection on CNS compartments like the hippocampus in future investigations. As a result of what happened in the hippocampus secondary to COVID-19, memory impairment may be a long-term neurological complication which can be a predisposing factor for neurodegenerative disorders through neuroinflammation and oxidative stress mechanisms.

Hesperetin, a Citrus Flavonoid, Ameliorates Inflammatory Cytokine-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation.

Oligodendrocytes (oligodendroglial cells) are glial cells that wrap neuronal axons with their differentiated plasma membranes called myelin membranes. In the pathogenesis of inflammatory cytokine-related oligodendroglial cell and myelin diseases such as multiple sclerosis (MS), typical inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) are thought to contribute to the degeneration and/or progression of the degeneration of oligodendroglial cells and, in turn, the degeneration of naked neuronal cells in the central nervous system (CNS) tissues. Despite the known involvement of these inflammatory cytokines in disease progression, it has remained unclear whether and how TNFα or IL-6 affects the oligodendroglial cells themselves or indirectly. Here we show that TNFα or IL-6 directly inhibits morphological differentiation in FBD-102b cells, which are differentiation models of oligodendroglial cells. Their phenotype changes were supported by the decreased expression levels of oligodendroglial cell differentiation and myelin marker proteins. In addition, TNFα or IL-6 decreased phosphorylation levels of Akt kinase, whose upregulation has been associated with promoting oligodendroglial cell differentiation. Hesperetin, a flavonoid mainly contained in citrus fruit, is known to have neuroprotective effects. Hesperetin might also be able to resolve pre-illness conditions, including the irregulated secretion of cytokines, through diet. Notably, the addition of hesperetin into cells recovered TNFα- or IL-6-induced inhibition of differentiation, as supported by increased levels of marker protein expression and phosphorylation of Akt kinase. These results suggest that TNFα or IL-6 itself contributes to the inhibitory effects on the morphological differentiation of oligodendroglial cells, possibly providing information not only on their underlying pathological effects but also on flavonoids with potential therapeutic effects at the molecular and cellular levels.

Pharmacological inhibition of Na+/K+-ATPase induces neurovascular degeneration and glial cell alteration in the rat retina

Na+/K+-ATPase (NKA) plays an important role in ion homeostasis and neurotransmitter uptake. In the retina, multidirectional communications among neurons, glia, and blood vessels (that is, neuro-glio-vascular interaction) are crucial for maintaining tissue homeostasis. We investigated the role of NKA in the elements of neuro-glio-vascular unit in neonatal and adult rat retinas. Male Sprague-Dawley rats (1- and 8-week-old) were injected intravitreally with ouabain (20 nmol/eye), an inhibitor of NKA. Morphological changes in retinal neurons, glia, and blood vessels were examined. The intravitreal injection of ouabain decreased the number of cells in the ganglion cell layer, as well as the thicknesses of the inner plexiform and inner nuclear layers in neonatal and adult rats compared to age-matched controls. The ouabain-induced neuronal cell damage was partially prevented by D-(−)-2-amino-5-phosphonopentanoic acid, an antagonist of N-methyl-D-aspartic acid receptors. In the deep retinal vascular plexus of the ouabain-injected eyes, angiogenesis was delayed in neonatal rats, whereas capillary degeneration occurred in adult rats. The immunoreactivity of glutamine synthetase and vascular endothelial growth factor (VEGF) decreased in the retinas of neonatal and adult rats injected intravitreally with ouabain. The immunoreactivity of glial fibrillary acidic protein was enhanced in the retinas of ouabain-injected adult eyes. After the ouabain injection, CD45-positive leukocytes and Iba1-positive microglia increased in the inner retinal layer of neonatal rats, whereas they increased in the middle retinal layer of adult rats. These results suggest that the inhibition of NKA induces the degeneration of neuronal and vascular cells and alteration of glial cells in both neonatal and adult retinas. In addition to the direct effects of NKA inhibition, the disturbance of retinal glutamate metabolism and decreased VEGF expression may contribute to neurovascular degeneration. The activity of NKA is crucial for maintaining elements of neuro-glio-vascular unit in the retina.

Macular thickness assessment in diabetic patients without retinopathy

ObjectiveA comparative study of macular thickness measurements with optical coherence tomography (OCT) in patients with diabetes mellitus without diabetic retinopathy (DR) versus healthy controls.BackgroundDR is one of the most common causes of deterioration of vision in the adult population. Recently, some studies showed that the degeneration of the retinal neuronal cells starts before the microvascular changes appear clinically.Patients and methodsSixty-five patients with diabetes mellitus (without DR underwent full ophthalmic examination; colored fundus photography, fluorescin fundus angiography, and OCT. Mean macular thickness measured by OCT was calculated for the central fovea, the perifoveal, and the parafoveal area of the macula which compared to healthy controls.ResultsThe mean central foveal retinal thickness (RT) of patients without DR shows to be thinnest when compared to the healthy group, which is statistically significant. The perifoveal retinal thickness of patients without DR proves to be the thinnest when compared to the healthy group, which is statistically highly significant. While, in the parafoveal macular zone, no statistically significant difference in RT could be detected between both groups.ConclusionThis results support the view of neurodegeneration in diabetes in the early stage of retinopathy which show a highly significantly decrease in perifoveal RT in patients without DR compared to healthy controls.

Neuroprotective effects of thymoquinone against MDMA-induced neurotoxicity

MDMA (3, 4-methylenedioxymethamphetamine) is a psychoactive substance that is associated with neurotoxicity. MDMA exposure to human results in the degeneration of neuronal cells in the hippocampus. Hence, the purpose of this study was to examine the potential of a natural compound known as thymoquinone (TQ) to protect against neuronal damage and memory impairment in rats stimulated by MDMA. The administration of TQ into MDMA-induced neuronal damage rats was carried out in male Sprague Dawley via a 1-week treatment dividing into four groups (n=36, 7-9 per group). The studied groups involved with the treatments comprise i) Control (1 mL/kg saline), ii) MDMA (10 mg/kg MDMA), iii) MDMA+TQ (10 mg/kg MDMA + 40 mg/kg TQ) and iv) TQ control (40 mg/kg TQ). A novel object recognition test (NORT) was carried out to evaluate the memory performance of the rats, followed by a histopathological assessment of the hippocampal dentate gyrus. The histopathology analysis revealed a significant increase in numbers of positive cells by Fluoro-Jade C following the effect of MDMA on neuronal damage (MDMA induced group) compared to control (P<0.05). Next, the TQ treatments observed in MDMA+TQ exhibited a decline in positive cells from Fluoro-Jade C. The index of recognition memory was found to be increased in MDMA+TQ compared to the MDMA alone (P<0.05). This study suggests that the neuronal damage inflicted by MDMA in a rat model has the potential to be treated by TQ.

Is the commonly used UV filter benzophenone-3 a risk factor for the nervous system?

Benzophenone-3 (2-hydroxy-4-methoxybenzophenone, oxybenzone, or BP-3) is one of the most frequently used UV radiation absorbents, which are commonly referred to as sunscreen filters. Its widespread use in industrial applications provides protection against the photodegradation of a wide range of products but at the same time creates the risk of human exposure to benzophenone-3 unbeknownst to the individuals exposed. Topically applied benzophenone-3 penetrates individual skin layers, enters the bloodstream, and is excreted in the urine. In addition, benzophenone-3 easily crosses the placental barrier, which creates the risk of exposure to this substance in the prenatal period. Despite the widespread use and occurrence of benzophenone-3 in the human environment, little knowledge of the mechanisms underlying the effect of benzophenone-3 on the nervous system was available until recently. Only the most recent research, including studies by our group, has enabled the identification of new molecular mechanisms through which benzophenone-3 affects embryonic neuronal cells and the developing mammalian brain. Benzophenone-3 has been shown to induce neurotoxicity and apoptotic processes and inhibit autophagy in embryonic neuronal cells. Benzophenone-3 also alters expression and impairs function of receptors necessary for the proper development and function of the nervous system. The most worrying finding seems to be that benzophenone-3 contributes to an increased risk of developmental abnormalities and/or epigenetically based degeneration of neuronal cells by changing the epigenetic status of neuronal cells.

Expanding the Arsenal Against Huntington's Disease-Herbal Drugs and Their Nanoformulations.

Huntington’s disease (HD) is an autosomal fatal genetic disease in which degeneration of neuronal cells occurs in the central nervous system (CNS). Commonly used therapeutics are cludemonoamine depletors, antipsychotics, antidepressants, and tranquilizers. However, these drugs cannot prevent the psychotic, cognitive, and behavioral dysfunctions associated with HD. In addition to this, their chronic use is limited by their long-term side effects. Herbal drugs offer a plausible alternative to this and have shown substantial therapeutic effects against HD. Moreover, their safety profile is better in terms of side effects. However, due to limited drug solubility and permeability to reach the target site, herbal drugs have not been able to reach the stage of clinical exploration. In recent years, the paradigm of research has been shifted towards the development of herbal drugs based nanoformulations that can enhance their bioavailability and blood-brain barrier permeability. The present review covers the pathophysiology of HD, available biomarkers, phytomedicines explored against HD, ongoing clinical trials on herbal drugs exclusively for treating HD and their nanocarriers, along with their potential neuroprotective effects.

Effects of doxorubicin on the developing brain of albino mice embryos

Introduction: Doxorubicin is an anthracycline antineoplastic drug. It has been widely used in the treatment of many malignancies including haematological malignancies, soft tissues sarcomas, breast cancer and neuro-blastoma etc. The doxorubicin rat model is an established model which encompasses spectrum of anomalies seen in VACTERAL associations and has similarities to human VACTER anomalies. The aim of present study is to support the anomalies produced by doxorubicin in albino mice embryos. Material and Methods: The present study was conducted in the department of anatomy, IMS, BHU Varanasi, U.P, on fifty female albino mice of an average age of 80 to 100 days, kept in plastic cage with male (3female:1male) in aseptic air condition. After confirming the pregnancy, the drug was administered intraperitoneally on the 8th day of gestation in a dose of 3mg/kg body weight. The foetuses were collected by exteriorization of uterine horn on 19th day of gestation and examined for congenital anomalies. Observations:Foetuses were divided into two groups, control and treated. Out of 239 treated foetuses, 25 foetuses were found dead, 106 foetuses showed congenital anomalies and the rest 108 foetuses were found normal. The brains of treated foetuses were smaller and reduced in weight (microcephaly) as compared to average weight and size of brain of control foetuses. On histological examination, cerebrum and cerebellum showed degeneration and aggregation of neuronal cells. Conclusions:The drug was found to be lethal as well as teratogenic in developing mice embryos. adriamycine rat model for VACTERL anomalies. Since, mice are the foremost mammal model for researchers; the present study also establishes doxorubicin mouse model support to the well established. Keywords:Doxorubicin (Adriamycine), VACTERL (Vertebral, anal, Cardiac, Tracheal, Oesophageal, Renal & limb) anomalies.

Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs.

Differential temporal and spatial post-injury alterations in cerebral cell morphology and viability.

Combination of ischemia and β-amyloid (Aβ) toxicity has been shown to simultaneously increase neuro-inflammation, endogenous Aβ deposition, and neurodegeneration. However, studies on the evolution of infarct and panorama of cellular degeneration as a synergistic or overlapping mechanism between ischemia and Aβ toxicity are lacking. Here, we compared fluorojade B (FJB) and hematoxylin and eosin (H&E) stains primarily to examine the chronology of infarct, and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post Aβ toxicity and endothelin-1 induced ischemia (ET1) in rats. We demonstrated a regional difference in cellular degeneration between cortex, corpus callosum, striatum, globus pallidus, and thalamus after cerebral injury. Glial cells in the cortex and corpus callosum underwent delayed FJB staining from d7 to d28, but neurons in cortex disappeared within the first week of cerebral injury. Striatal lesion core and globus pallidus of Aβ + ET1 rats showed extensive degeneration of neuronal cells compared with ET1 rats alone starting from d1. Differential and exacerbated expressions of cyclooxygenase-2 might be the cause of excessive neuronal demise in the striatum of Aβ + ET1 rats. Such an investigation may improve our understanding to identify and manipulate a critical therapeutic window post comorbid injury.

Immunotoxicological Investigation of The Intracranial Auditory Centers In Pyrethroids Formulation Treated Wistar Rat

Purpose: The use of pesticides and their potential impact on public health are of great concern. Recent studies on the pathophysiology of neurodegenerative diseases have suggested that chronic exposure to pyrethroids could be associated with alterations in the central auditory pathways. This study was therefore aimed at evaluating the neurotoxicity of pyrethroids on the intracranial auditory relay-centers in adult wistar rats. Methods: Forty adult wistar rats of both sexes with average weight of 180g were assigned into five groups (n=8). Groups A, B, and C were treated with known pyrethroids formulation containing Cyfluthrin, Imiprothrin, and Prallethrin, diluted with olive oil to form 25%, 50% and 75% concentrations. Groups D and E were administered distilled water and olive oil once treatment negative and positive controls, respectively. The treatment lasted for duration of forty days. At the end of the duration, all animals were sacrificed by cervical dislocation, after which the inferior colliculi (IC), medial geniculate bodies (MGB) and cerebellum were harvested for histology and immuno histochemistry using calbindin and palvalbumin antibodies. Results: Histologically, there was slight degeneration of neuronal cells and vacuolated cytoplasm, dispersed distribution of nissl bodies in several cells of MGB and IC of the treated groups compared to the controls. In the cerebellum, there was abnormal proliferation of cells in the purkinje layer with poor distribution of nissl bodies when compared to control groups. Immuno histochemistry further revealed decreased immuno-reactivity of Calbindin2 and Parvalbumin in the treated tissues compared to the control groups. Conclusion: Pyrethroids influences motor coordination and balance of rats, and also the function of the auditory relay-centres.

Anatomical Basis of Epileptogenesis in a Mouse Model of Traumatic Brain Injury

Post‐traumatic epilepsy (PTE) is characterized by progressive spontaneous recurrent seizures (SRS) following traumatic brain injury (TBI). PTE is poorly controlled by current medications and the molecular pathophysiology of PTE is unclear. A critical step for preventing PTE is to determine a key pathway that drives disease progression during the “latent period” after TBI, termed epileptogenesis. The potential mechanisms of underlying post‐traumatic epileptogenesis include neuroinflammation, degeneration of neuronal cells, and alterations in the hippocampal neurogenesis and mossy fiber sprouting. In this study, we sought to demonstrate a causal anatomical relationship between neuroinflammation and/or neurodegeneration and the onset of PTE in mice. TBI was induced in mice by a controlled‐cortical impact paradigm and were then monitored by video‐EEG recording for 120 days with a deep electrode placed within the contralateral hippocampus. At days 1, 3, 7, 30, 60, 120 post‐TBI, brains were fixed for immunohistochemistry and analyzed for principal neurons (NeuN+), interneurons (PV+), astrogliosis (GFAP+), microgliosis (IBA1+), and neurogenesis (DCX). Alterations in hippocampal and hemispheric architecture were visualized with quantitative analysis. Pronounced atrophy was evident within the ipsilateral hemisphere in the form of large lesions which extended from the cortex to the hippocampus by 120 days. In the contralateral hippocampus, inflammatory markers of microgliosis and astrogliosis reached peak levels within the first week before steadily declining throughout the 120‐day observation period. In contrast, neurodegeneration of NeuN+ cells and PV+ interneurons was not evident at these early stages, but cell loss became unmistakable starting 30 days post‐TBI. By this point, nearly 30% of PV+ interneurons were lost, with the dentate gyrus serving as the greatest region of cell loss (~40% loss). These studies were repeated using a moderate 1mm injury to emphasize the relationship between injury severity and neurodegeneration. Our findings are reminiscent of preferential loss of inhibitory interneurons in epilepsy patients and suggest that early neuroinflammation may catapult neurodegeneration within the damaged areas, which appears to be a critical mechanism for the onset of epileptogenesis. Specifically, progressive loss of PV+ GABAergic interneurons within the dentate gyrus correlates with progression of SRS from 30 to 60 days, coinciding with the onset of SRS at 39 days post‐TBI.Support or Funding Information**Funded by DOD Award #W81XWH‐16‐1‐0660**

Supplementation with Curcuma longa Reverses Neurotoxic and Behavioral Damage in Models of Alzheimer's Disease: A Systematic Review.

Background: The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer’s disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases.Objective: The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD.Method: This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: “Curcuma longa”, “Curcumin” and “Alzheimer’s disease”.Results: A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD.Conclusion: The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

An overview of the neuroprotective potential of rosmarinic acid and its association with nanotechnology-based delivery systems: A novel approach to treating neurodegenerative disorders

Neurodegenerative disorders (ND) are characterized by slow and progressive neuronal dysfunction induced by the degeneration of neuronal cells in the central nervous system (CNS). Recently, the neuroprotective effects of natural compounds with anti-inflammatory and antioxidant activities has been clearly demonstrated. This appears to be an attractive therapeutic approach for ND, particularly regarding the use of polyphenols. In this review, we present an overview of the neuroprotective potential of rosmarinic acid (RA) and discuss the use of nanotechnology as a novel approach to treating ND. RA presents a variety of biological important activities, i.e. the modulation of pro-inflammatory cytokine expression, prevention of neurodegeneration and damage reduction. However, its poor bioavailability represents a limitation in terms of pharmacodynamics. In this sense, nanotechnology-based carriers could allow for the administration of higher but still safe amounts of RA, aiming for CNS delivery. Nasal administration could be a pleasant route for delivery to the CNS, as this represents a direct route to the CNS. With these advantages, RA-loaded nanotechnology-based therapy through the nasal route could be promising approach for the treatment of ND.

\u03b11-antitrypsin mitigates NLRP3-inflammasome activation in amyloid \u03b21\u201342-stimulated murine astrocytes

BackgroundNeuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β1–42 (Aβ1–42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD.The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ1–42-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ1–42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT.MethodsPrimary cortical astrocytes from BALB/c mice were stimulated with Aβ1–42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components.ResultsOur study revealed that A1AT reduces Aβ1–42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ1–42-stimulated astrocytes.ConclusionWe conclude that Aβ1–42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ1–42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease.

Sphingosine kinase 1/sphingosine-1-phosphate receptors dependent signalling in neurodegenerative diseases. The promising target for neuroprotection in Parkinson's disease.

Parkinson's disease (PD) is one of the most common serious neurodegenerative disorders in the world. The incidence of PD appears to be growing and this illness has an unknown pathogenesis. PD is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra (SN), with an enigmatic cause in most individuals. Current pharmacotherapies and surgery provide symptomatic relief but their effects against the progressive degeneration of neuronal cells are strongly limited if present at all. Therefore, uncovering novel molecular mechanisms of DA cell death and new potentially disease-modifying pharmacological targets is an important task for basic research. Significant progress has been made in understanding the role of disturbed sphingolipid metabolism, particularly relating to ceramide and sphingosine-1-phosphate (S1P) in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative diseases. Additionally, the neuroprotective potential of an S1P receptors (S1PR) modulator, fingolimod (FTY720), in multiple sclerosis (MS) and numerous other diseases has been observed over the past decade. In this review, we briefly summarise recent achievements in defining intracellular S1PR-dependent actions, discuss their significance to therapeutic approaches, and explore their neuroprotective potential as a target in PD treatment.