RESUMO
Aluminum is a potent neurotoxin, responsible for memory impairment and cognitive dysfunction. The neurotoxic effect of aluminum on cognitive impairment is well documented, however, exposure to aluminum in a time-dependent manner and post-exposure self-recovery still needs to be elaborated. This research aimed to (1) study the time-dependent effect of aluminum exposure by administering a total dose of 5850 mg/kg of Al over two different time periods: 30 and 45 days (130 and 195 mg/kg of AlCl3 respectively), and (2) study 20 days post-exposure self-recovery effect in both aluminum-exposed groups by giving distilled water. Cognitive abilities were investigated through Morris water maze test and hole board test and compared in both exposure and recovery groups. Oxidative stress markers and neurotransmitter levels were measured for both exposure and recovery groups. To understand the mechanism of aluminum exposure and recovery, immunohistochemical analysis of synaptophysin (Syp) and glial fibrillary acidic protein (GFAP) was performed. Results showed cognitive dysfunction, oxidative stress-induced damage, reduced neurotransmitter levels, decreased immunoreactivity of Syp, and increased GFAP. However, these parameters showed a larger improvement in the recovery group where rats were given aluminum for 30 days period in comparison to recovery group followed by 45 days of aluminum exposure. These results suggest that restoration of cognitive ability is affected by the duration of aluminum exposure. The study findings provide us with insight into the adverse effects of aluminum exposure and can be utilized to guide future preventive and therapeutic strategies against aluminum neurotoxicity.
Assuntos
Alumínio , Neurotransmissores , Estresse Oxidativo , Ratos Wistar , Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Masculino , Alumínio/toxicidade , Neurotransmissores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Memória Espacial/efeitos dos fármacos , Sinaptofisina/metabolismo , Fatores de Tempo , Proteína Glial Fibrilar Ácida/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Cloreto de AlumínioRESUMO
Aluminum is a ubiquitous metal that causes multiple brain pathologies such as, cognitive dysfunction and Alzheimer's disease like symptoms. Exposure to aluminum through drinking water is responsible for hampering learning and memory. This study aimed to compare (1) the time-dependent effect of aluminum exposure (keeping total exposure of 5850 mg/kg same) in two durations, 30 and 45 days, and (2) to compare post-exposure self-recovery effect after 20 days in both (30 and 45 days exposure) groups. Rats were given 130 and 195 mg/kg of AlCl3·6H2O for 45 and 30 days respectively, to see the time-dependent exposure effect. At the end of exposure, rats were given distilled water and allowed to self-recover for 20 days to study the recovery. Expression levels of synaptic genes (Syp, SNAP25, Nrxn1/2, PSD95, Shank1/2, Homer1, CamkIV, Nrg1/2 and Kalrn) were measured using qPCR and compared in the exposure and recovery groups. Cellular morphology of the rat brain cortex and hippocampus was also investigated. Damage in lipid and protein profile was measured by employing FTIR. Results showed downregulation of mRNA expression of synaptic genes, plaques deposition, disorganization in lipid and protein profile by increasing membrane fluidity, and disorder and alteration of protein secondary structure after both exposure periods. However, better improvement/recovery in these parameters were observed in recovery group of 30 days aluminum exposure compared to 45 days aluminum exposure group. Taken together, these results suggested that short-term exposure resulted in better restoration of lipid and protein profile after time-dependent exposure of aluminum than prolonged exposure.
Assuntos
Alumínio , Doença de Alzheimer , Animais , Ratos , Alumínio/toxicidade , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , LipídeosRESUMO
Aluminum (Al) is known for its neurotoxicity for over a century and is reported to have specifically high toxicity for cholinergic system. The effect of Al on muscarinic acetylcholine receptors is widely reported, but its effect on nicotinic acetylcholine receptors (nAChRs) is less well known. The aim of this study was to determine the effects of Al on hippocampus dependent learning and memory, function and expression of nAChRs in the hippocampus. Al concentration and neurodegeneration were also measured in the hippocampus following Al treatment. The mice were treated with 250 mg/kg AlCl3.6H2O in drinking water for a period of 42 days. Results show that Al treated animals have significantly reduced spatial reference memory as compared to control animals in Morris water maze test. Similarly, Al treated animals showed reduced contextual memory for Pavlovian fear compared to control animals. Al treated animals show higher anxiety in elevated plus maze as compared to control animals. The analysis of nAChR expression via RT-PCR showed reduced expression of α7, α4 and ß2 nAChR gene expression in the hippocampus of Al treated animals. High Al accumulation was observed in Al-treated animals (688.14 ± 242.82 µg/g) compared to the control group (115.14 ± 18.18 µg/g) that resulted in severe neurodegeneration in the hippocampus. These results demonstrated that Al exposure caused neurotoxicity in mice hippocampus which is manifested by reduced memory and elevated anxiety. The results were further validated by high Al accumulation in the hippocampus, severe neurodegeneration and reduced expression of nAChRs.
Assuntos
Cloreto de Alumínio/toxicidade , Hipocampo/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Receptores Nicotínicos/genética , Administração Oral , Cloreto de Alumínio/administração & dosagem , Animais , Ansiedade/induzido quimicamente , Medo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Síndromes Neurotóxicas/fisiopatologia , Memória Espacial/efeitos dos fármacosRESUMO
Aging is known to be one of the major risk factors in many neurodegenerative diseases (ND) whose prevalence is estimated to rise in the coming years due to the increase in life expectancy. Examples of neurodegenerative diseases include Huntington's, Parkinson's, and Alzheimer's diseases, along with Amyotrophic Lateral Sclerosis, Spinocerebellar ataxias and Frontotemporal Dementia. Given that so far these ND do not have effective pharmacological therapies, a better understanding of the molecular and cellular mechanisms can contribute to development of effective treatments. During the previous decade, the data indicated that dysregulation of MAP kinases [which included c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and p38] are associated with several stages of the inflammatory process which in turn contributes to age-related neurodegenerative diseases. This evidence suggests that control of inflammation through regulation of MAP kinase could be a worthwhile approach against neurodegenerative diseases. In this review we summarize the pathways of MAP kinase signal transduction and different pharmacological inhibitors that can be used in its modulation against ND.
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Anti-Inflamatórios/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Degeneração Neural , Doenças Neurodegenerativas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Anti-Inflamatórios/efeitos adversos , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de SinaisRESUMO
Autophagy is an important biological mechanism involved in the regulation of numerous fundamental cellular processes that are mainly associated with cellular growth and differentiation. Autophagic pathways are vital for maintaining cellular homeostasis by enhancing the turnover of nonfunctional proteins and organelles. Neuronal cells, like other eukaryotic cells, are dependent on autophagy for neuroprotection in response to stress, but can also induce cell death in cerebral ischemia. Recent studies have demonstrated that autophagy may induce neuroprotection following acute brain injury, including ischemic stroke. However in some special circumstances, activation of autophagy can induce cell death, playing a deleterious role in the etiology and progression of ischemic stroke. Currently, there are no therapeutic options against stroke that demonstrate efficient neuroprotective abilities. In the present work, we will review the significance of autophagy in the context of ischemic stroke by first outlining its role in ischemic neuronal death. We will also highlight the potential therapeutic applications of pharmacological modulators of autophagy, including some naturally occurring polyphenolic compounds that can target this catabolic process. Our findings provide renewed insight on the mechanism of action of autophagy in stroke together with potential neuroprotective compounds, which may partially exert their function through enhancing mitochondrial function and attenuating damaging autophagic processes.
Assuntos
Autofagia , Neuroproteção , Acidente Vascular Cerebral/terapia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Humanos , Camundongos , Neurônios/citologia , Neurônios/fisiologia , Acidente Vascular Cerebral/metabolismoRESUMO
JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.
Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Fatores de Transcrição STAT/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Humanos , Inflamação/metabolismo , Doenças do Sistema Nervoso/metabolismo , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Fatores de Transcrição STAT/química , Fatores de Transcrição STAT/metabolismoRESUMO
BACKGROUND: Mild cognitive impairment (MCI) is becoming an emerging problem for developing countries where there is an increase in expected age. There is no specific curative therapeutic treatment available for these patients. OBJECTIVE: The objective of this study was to evaluate short and long-term changes in the electroencephalogram (EEG) parameters and cognition of MCI patients with aerobic exercises. METHODS: A randomized controlled trial was conducted on 40 patients which were randomly divided into two groups, 'aerobic exercise treatment group (n = 21)' and 'no-aerobic control group (n = 19)'. Short-term effects of exercise were measured after single session of exercise and long-term effects were measured after an 18 sessions (6 weeks) treatment. The outcomes which were measured were, electroenphelogram paramaters (slowness and complexity of the EEG) and cognitive functions (using mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), and trail making test (TMT) A and B). RESULTS: After one session of aerobic exercise there were significant improvements in slowness (delta waves; 0.678 ± 0.035 vs 0.791 ± 0.033; p = .015) and complexity (0.601 ± 0.051 vs 0.470 ± 0.042; p = .027) of the EEG in aerobic exercise treated group as compared to no-aerobic exercise group. After six weeks there were significant improvements in slowness (delta waves; 0.581 ± 0.036 vs 0.815 ± 0.025; p = .005) and complexity (0.751 ± 0.045 vs 0.533 ± 0.046; p = .001) of the EEG in the aerobic group as compared to no-aerobic group. Moreover, significant improvements were observed in the MMSE (p = .032), MoCA (p = .036), TMT-A (p = .005), and TMT-B (p = .007) in aerobic exercise group as compared to no-aerobic group. CONCLUSION: Aerobic exercise showed improvement in cognition after short and long-term treatment in MCI subjects and can be used as potential therapeutic candidate.
Assuntos
Cognição , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/terapia , Eletroencefalografia , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes NeuropsicológicosRESUMO
The present study investigates the neuroprotective effects of Foeniculum vulgare seeds in a lead (Pb)-induced brain neurotoxicity mice model. The dried seeds extract of Foeniculum vulgare was prepared with different concentrations of organic solvents (ethanol, methanol, n-hexane). The in vitro antioxidant activity of Foeniculum vulgare seed extracts was assessed through DPPH assay and the chemical composition of the extracts was determined by high-resolution 1H NMR spectroscopy. The age-matched male Balb/c mice (divided into 9 groups) were administered with 0.1% Pb and 75% and 100% ethanol extracts of Foeniculum vulgare seeds at a dose of 200 mg/kg/day and 20 mg/kg/day. The maximum antioxidant activity was found for 75% ethanol extract, followed by 100% ethanol extract. Gene expression levels of oxidative stress markers (SOD1 and Prdx6) and the three isoforms of APP (APP common, 770 and 695), in the cortex and hippocampus of the treated and the control groups were measured. Significant increase in APP 770 expression level while a substantial decrease was observed for SOD1, Prdx6 and APP 695 expression in Pb-treated groups. Interestingly, the deranged expression levels were significantly normalized by the treatment with ethanol extracts of Foeniculum vulgare seeds (specifically at dose of 200 mg/kg/day). Furthermore, the Pb-induced morphological deterioration of cortical neurons was significantly improved by the ethanol extracts of Foeniculum vulgare seeds. In conclusion, the present findings highlight the promising therapeutic potential of Foeniculum vulgare to minimize neuronal toxicity by normalizing the expression levels of APP isoforms and oxidative stress markers.
Assuntos
Encéfalo/efeitos dos fármacos , Foeniculum , Chumbo/toxicidade , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Extratos Vegetais/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Foeniculum/química , Sequestradores de Radicais Livres/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , SementesRESUMO
UNLABELLED: Aluminium metal (Al) has been implicated in the etiology of many neurodegenerative diseases, most commonly the Alzheimer's disease (AD). Al causes biochemical defects by affecting the neurotransmitters level, causes conformational changes in amyloid ß protein and increases amyloid accumulation in brain. AIM: This study was aimed at evaluating neuroprotective effect of Ibuprofen (IBU) (25 mg/kg/day for 12 days) in AlCl3-induced (150 mg/kg/day for 12 days) toxicity. METHODS: Treated mice were subjected to learning and memory tests. Cholinergic muscarinic receptors (mAChR; M1-M5) and APP isoforms (APP695, APP770 and APP common) gene expression were carried out from the pre-frontal cortex area. RESULTS: Profound effect on learning and memory was observed in IBU treated group along with enhanced expression of M1 mAChR (0.40 ± 0.03; p < 0.01) compared to AlCl3-induced toxicity group (0.05 ± 0.02). Fear memory was improved in IBU treated group (89.68 ± 2.58, p < 0.01) as compared to AlCl3-induced toxicity group (54.58 ± 8.21). Discrimination index in social novelty test in IBU treated group was improved (81.13 ± 8.71; p < 0.05), compared to AlCl3-induced toxicity group (46.28 ± 5.55). Similarly, recognition memory of IBU treated group in novel object recognition test (NOB) was retained (66.85 ± 5.60; p < 0.05) as compared to AlCl3-induced toxicity group (33.06 ± 11.80). CONCLUSION: IBU demonstrated memory enhancing effect, however, its effect on the APP isoforms expression in pre-frontal cortex needs further studies.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Ibuprofeno/uso terapêutico , Deficiências da Aprendizagem/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Córtex Pré-Frontal/metabolismo , Receptores Muscarínicos/metabolismo , Cloreto de Alumínio , Compostos de Alumínio/toxicidade , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Adstringentes/toxicidade , Cloretos/toxicidade , Condicionamento Clássico/efeitos dos fármacos , Modelos Animais de Doenças , Medo , Regulação da Expressão Gênica/efeitos dos fármacos , Ibuprofeno/farmacologia , Deficiências da Aprendizagem/induzido quimicamente , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos BALB C , Comportamento de Nidação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores Muscarínicos/genética , Comportamento SocialRESUMO
Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Curcuma/química , Curcumina/análogos & derivados , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Diarileptanoides , Humanos , Estrutura Molecular , FitoterapiaRESUMO
Exposure to neurotoxic and heavy metals (Pb2+, As3+, Mn2+, Cd2+, etc) has increased over time and has shown to negatively affect brain health. Heavy metals can cross the blood brain barrier (BBB) in various ways including receptor or carrier-mediated transport, passive diffusion, or transport via gaps in the endothelial cells of the brain. In high concentrations, these metals have been shown to cause structural and functional impairment to the BBB, by inducing oxidative stress, ion dyshomeostasis, tight junction (TJ) loss, astrocyte/pericyte damage and interference of gap junctions. The structural and functional impairment of the BBB results in increased BBB permeability, which ultimately leads to accumulation of these heavy metals in the brain and their subsequent toxicity. As a result of these effects, heavy metals are correlated with various neurological disorders. The pathological effects of these heavy metals can be effectively mitigated via chelation. In addition, it is possible to treat the associated disorders by counteracting the molecular mechanisms associated with the brain and BBB impairment.
Assuntos
Barreira Hematoencefálica , Metais Pesados , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Humanos , Animais , Metais Pesados/toxicidade , Estresse Oxidativo/efeitos dos fármacosRESUMO
Traumatic brain injury (TBI) is associated with the etiology of multiple neurological disorders, including neurodegeneration, leading to various cognitive deficits. Daidzin (obtained from kudzu root and soybean leaves) is known for its neuroprotective effects through multiple mechanisms. This study aimed to investigate the pharmacological effects of Daidzin on sensory, and biochemical parameters, cognitive functions, anxiety, and depressive-like behaviors in the TBI rat model. Rats were divided into four groups (Control, TBI, TBI + Ibuprofen (30â¯mg/kg), and TBI + Daidzin (5â¯mg/kg)). Rats were subjected to TBI by dropping a 200â¯g rod from a height of 26â¯cm, resulting in an impact force of 0.51â¯J on the exposed crania. Ibuprofen (30â¯mg/kg) was used as a positive control reference/standard drug and Daidzin (5â¯mg/kg) as the test drug. Neurological severity score (NSS) assessment was done to determine the intactness of sensory and motor responses. Brain tissue edema and acetylcholine levels were determined in the cortex and hippocampus. Cognitive functions such as hippocampus-dependent memory, novel object recognition, exploration, depressive and anxiety-like behaviors were measured. Treatment with Daidzin improved NSS, reduced hippocampal and cortical edema, and improved levels of acetylcholine in TBI-induced rats. Furthermore, Daidzin treatment improved hippocampus-dependent memory, exploration behavior, and novel object recognition while reducing depressive and anxiety-like behavior. Our study revealed that Daidzin has a therapeutic potential comparable to Ibuprofen and can offer neuroprotection and enhanced cognitive and behavioral outcomes in rats after TBI.
Assuntos
Comportamento Animal , Lesões Encefálicas Traumáticas , Modelos Animais de Doenças , Fármacos Neuroprotetores , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/complicações , Ratos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Ibuprofeno/farmacologia , Ibuprofeno/administração & dosagem , Ansiedade/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Cognição/efeitos dos fármacos , Depressão/tratamento farmacológico , Depressão/etiologia , Ratos Wistar , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologiaRESUMO
Fiber reinforced concrete (FRC) is attracting many researchers' attention due to its excellent mechanical and fracture properties. However, its widespread implementation is hampered by the issues related to the dispersion and orientation of its fibers. According to the fracture mechanics, the reinforcement would provide maximum bridging when placed perpendicular to the crack propagation. This study is focused on the magnetic-based orientation of synthetic fibers which are mostly used in strain hardening FRC also termed as Engineered Cementitious Composites (ECC). Initially, the PVA fibers were coated with waste iron particles using a hydrothermal synthesis procedure. This was done to make synthetic fibers magnetically responsive by the formation of a physical bond between iron and PVA fibers. A solenoid was used to provide a high-intensity magnetic flux to orient these fibers in the direction of magnetic lines. Three different ECC mixes were prepared and cast in wooden molds. The molds were then placed one by one into the magnetic field for the orientation of the fibers. The fibers were successfully aligned perpendicular to the flexure cracks in only flexure dominant regions with the aid of a magnetic field. The orientation of fibers was verified with the help of microscopic images of the tortured surfaces. As a result of well aligned fibers dispersed in the ECC mix, the flexural strength was increased by 21%.
RESUMO
Traumatic brain injury (TBI) is a serious global risk factor leading to the onset of cognitive impairment and neurodegenerative diseases. Cognitive and memory impairment following a TBI is associated with the dysregulation of cholinergic neurotransmission in the brains of subjects. The extent of memory impairment following a TBI is linked with the sex of the subject. This study aimed to identify the sex-dimorphic role of muscarinic cholinergic modulation in neurological functioning and episodic memory retrieval in a mouse model of TBI. Balb/c mice were divided into four groups of males and four groups of females (i.e., Sham, TBI, TBI + Scopolamine 1 mg/kg, and TBI + Donepezil 1 mg/kg). After training with the Morris water maze test and fear conditioning, all groups were subjected to brain injury (7.84 × 10-5 J impact force) except for the Sham mice. Following brain injury, scopolamine or donepezil was administered to the respective groups for 5 days. Acute scopolamine immediately after brain trauma showed a neuroprotective effect in the males only, while subchronic donepezil significantly impaired neurological functioning in both sexes. Subchronic scopolamine and donepezil treatment reversed the TBI-induced retrograde amnesia for spatial memory in male mice. Contextual fear memory retrieval was not affected by the TBI and treatments in both sexes. Thus, we concluded that the sex-dimorphic response of the muscarinic receptors in TBI-induced memory impairment depends on the type of memory. This study highlights the potential for therapeutic modalities in TBI subjects.
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Social behavior is a complex term which involves different interactions between various individuals of a community. It is controlled by different neurotransmitter systems in a sexually dimorphic way. Certain environmental factors, like stress, cause various neurological disorders with associated social abnormalities in a sexually dimorphic way. Multiple drugs are used in clinical settings to treat behavioral disorders. However, the sexually dimorphic effects of these drugs, particularly on social behavior, still need to be studied. The present study was designed to investigate the sex-dependent effects of Risperidone, Donepezil, and Paroxetine in 8-12 weeks old male and female rats under normal and stressed conditions. There were four male and four female groups, i.e., control group (no drug treatment), Risperidone (3 mg/kg/day) treated group, Donepezil (5 mg/kg/day) treated group, and Paroxetine (10 mg/kg/day) treated group. Each group received its respective drug during phase 1 for 21 days, followed by a 10-day break with no drug treatment. After the break, same groups received the same drugs along with tilt-cage stress for an additional 21 days during phase 2. A social preference and novelty test was performed at the end of both phases (1 and 2). During phase 1, Risperidone treatment caused impaired social behavior and reduced locomotion in the male group only, compared to its control group. Donepezil treatment caused a reduction in social interaction, while Paroxetine treatment caused increased social interaction and locomotion in a sex-dependent manner. During phase 2, social novelty was affected in both male and female stress groups. Treatment with drugs along with stress showed differential sex-dependent effects. The study showed a predominant effect of Risperidone on males while there were differential effects of Donepezil and Paroxetine on both sexes. This study has paved the way for the development of more targeted and effective neuromodulatory drugs for use against various psychiatric and social deficits.
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BACKGROUND: Social hierarchies are important for individual's well-being, professional and domestic growth, harmony of the society, as well as survival and morbidity. Studies have revealed sexual dimorphism in the social abilities; however, data is limited on the sex-specific effects of various drugs used to treat psychiatric disorders and social deficits. OBJECTIVE: The present study aimed at evaluating the sex-dependent effects of Risperidone (antipsychotic that targets D2 dopaminergic, 5HT2A serotonergic, and α-adrenergic receptors), Donepezil (a reversible acetylcholinesterase inhibitor), and Paroxetine (a selective serotonin reuptake inhibitor) on social hierarchy in rats under normal and stressed states. METHODS: 8-12 weeks old male and female Wistar rats were divided into sex-wise 4-4 groups, i.e., 1. control group, 2. Risperidone treated group (3 mg/kg/day), 3. Donepezil treated group (5 mg/kg/day), and Paroxetine treated group (10 mg/kg/day). Rats were treated with these drugs in phase I for 21 days in distilled drinking water, followed by a no (drugs) treatment break of 10 days. After the break phase II started with the administration of drugs (same as in phase I) along with tilt-cage stress for 21 days. Home cage activity assessment was performed once a week during both phases (I & II), while tube dominance and resident intruder tests were performed at the end of each phase. RESULTS: In phase I in both sexes, Risperidone treatment decreased social interaction and motor activity while Paroxetine treatment increased these in both sexes compared to their respective control groups. Social dominance and aggression were reduced after treatment with both of these drugs. In contrast, Donepezil treatment caused an increase in motor activity in females whereas reduced motor activity in males. Furthermore, Donepezil treatment caused reduction in interaction but increased social dominance and aggression were observed in both sexes. In phase II, stress led to an overall decrease in motor activity and social interaction of animals. Treatment with Risperidone, Paroxetine, and Donepezil caused a sex-specific effect on, motor activity, social interaction, and social exploration. CONCLUSION: These results showed that Risperidone has stronger effects on male social behavior whereas Paroxetine and Donepezil differentially affect social abilities in both sexes during normal and stressed situations.
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BACKGROUND: Increased exposure of humans to toxic metals and high-fat diet (HFD) consumption severely damages brain health. Natural plant extracts have shown huge potential to treat multiple human diseases. OBJECTIVE: The present study was designed to evaluate the protective effects of Shogaol (an active component of ginger) in neuroinflammation and behavioral paradigms in mice treated with metals and HFD. METHODS: 8-11 weeks old male mice model was developed by giving a combination of metals, i.e., Arsenic (As), Lead (Pb) and Aluminum (Al), 25mg/kg each mixed in drinking water with laboratory prepared HFD (40% fat) for a total duration of 72 days. Shogaol treated groups received two doses (2mg/kg & 12mg/kg) of Shogaol along with metals and HFD. The biochemical parameters, including body weights, blood glucose, and kidney and liver functions, were assessed along with the integrity of the blood-brain barrier (BBB). The expression analysis of neuroinflammatory genes (TNF-α, IL-1ß & GFAP) was performed using q-PCR in the hippocampus and cortex. The exploratory and anxiety-like behavior was assessed using an open field test, and depressive behavior was assessed through the forced swim test, while learning and memory were assessed using the Morris water maze test and y-maze test. RESULTS: Shogaol (2mg/kg & 12mg/kg) treatment improved metabolic profile and reduced expression of neuroinflammatory genes in the cortex and the hippocampus. Shogaol treatment improved BBB integrity. Results of the behavioral analysis showed that Shogaol treatment (2mg/kg & 12mg/kg) rescued behavioral impairment and improved anxiety and depression. CONCLUSION: Shogaol treatment showed strong therapeutic potential in metals & HFD induced neuroinflammation and improved cognitive functions; thus, can be considered a potential drug candidate in the future.
Assuntos
Arsênio , Fármacos Neuroprotetores , Humanos , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Alumínio , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Chumbo , Doenças NeuroinflamatóriasRESUMO
Curcuminoids are vital constituent of turmeric, with therapeutic potential in the treatment of Alzheimer's disease. Electrically, stimulus train-elicited plastic changes in hippocampal CA1 excitability were used as an experimental paradigm to study the effects of curcuminoid mixture and individual components on functional failure induced by Aß peptide in vitro. Electrical stimulation was applied on Schaffer collaterals, and population spikes (PS) were recorded from stratum pyramidale. To induce long-term potentiation (LTP) of PS, primed burst stimulation (PBs) was used. Aß peptide inhibited PS LTP induction. Sinking PS LTP due to Aß peptide was rescued when curcuminoid mixture was applied before PBs only at lower dose (0.1 µM) resulting in PS potentiation to 127.42% ± 1.83% at 5 min and 123.98% ± 1.06% at 60-min post-PBs. Similarly, when bisdemethoxycurcumin was applied, PS LTP was induced and lasted only at a single dose (0.1 µM). Demethoxycurcumin was effective at a middle dose (1 µM), so that the PS amplitude was changed to 140.15% ± 2.68% and 129.82% ± 0.44% at 5 and 60 min, respectively. PS LTP was effectively induced in the presence of curcumin at middle and high doses (1 and 30 µM) with resultant PS LTP to 155.68% ± 1.23% and 127.72% ± 1.23%, respectively, at 60-min post-PBs. These results showed that curcuminoids can restore susceptibility for plastic changes in CA1 excitability that is injured by exposure to Aß peptide and rescue sinking PS LTP in Aß-peptide-exposed hippocampal CA1 neurons.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Curcumina/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Estimulação Elétrica , Eletrofisiologia , Masculino , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-DawleyRESUMO
Episodic memory retrieval is fundamental for daily activities of humans and animals. Muscarinic cholinergic signaling is important for memory functioning and shows gender-dependent response in episodic memory retrieval. Dopamine D2 receptors influence memory formation and retrieval by influencing cholinergic signaling in the brain. This study aimed to determine the gender-dependent effects of D2 and muscarinic activity on memory retrieval. Male and female mice were trained for Morris water maze test and contextual fear conditioning. Memory retrieval was assessed following sub-chronic treatment (for 5 days) with D2 antagonist (risperidone 2.5 mg/kg) alone or in combination with scopolamine (1 mg/kg) or donepezil (1 mg/kg). Open field test was performed prior to the retrieval test to evaluate effects of risperidone treatment on locomotor activity and exploratory behavior. Risperidone co-treatment with donepezil impaired spatial memory retrieval in males only. Muscarinic and D2 simultaneous antagonism tend to impair fear retrieval in males but significantly enhanced retrieval of fear memories in female mice. These results suggest that D2 signaling influence muscarinic receptor activity during memory retrieval in gender-dependent manner.
Assuntos
Medo/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores Muscarínicos/fisiologia , Caracteres Sexuais , Memória Espacial/fisiologia , Animais , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
Due to the exceptional qualities of fiber reinforced concrete, its application is expanding day by day. However, its mixed design is mainly based on extensive experimentations. This study aims to construct a machine learning model capable of predicting the fracture behavior of all conceivable fiber reinforced concrete subclasses, especially strain hardening engineered cementitious composites. This study evaluates 15x input parameters that include the ingredients of the mixed design and the fiber properties. As a result, it predicts, for the first time, the post-peak fracture behavior of fiber-reinforced concrete matrices. Five machine learning models are developed, and their outputs are compared. These include artificial neural networks, the support vector machine, the classification and regression tree, the Gaussian process of regression, and the extreme gradient boosting tree. Due to the small size of the available dataset, this article employs a unique technique called the generative adversarial network to build a virtual data set to augment the data and improve accuracy. The results indicate that the extreme gradient boosting tree model has the lowest error and, therefore, the best mimicker in predicting fiber reinforced concrete properties. This article is anticipated to provide a considerable improvement in the recipe design of effective fiber reinforced concrete formulations.