Neuroprotective mechanism of trans,trans-Farnesol in an ICV-STZ-induced rat model of Alzheimer's pathology.

BACKGROUND: Alzheimer's disease (AD) is a prominent cause of dementia, resulting in neurodegeneration and memory impairment. This condition imposes a considerable public health burden on both patients and their families due to the patients' functional impairments as well as the psychological and financial constraints. It has been well demonstrated that its aetiology involves proteinopathy, mitochondriopathies, and enhanced reactive oxygen species (ROS) generation, which are some of the key features of AD brains that further result in oxidative stress, excitotoxicity, autophagy, and mitochondrial dysfunction. OBJECTIVE: The current investigation was created with the aim of elucidating the neurological defence mechanism of trans,trans-Farnesol (TF) against intracerebroventricular-streptozotocin (ICV-STZ)-induced Alzheimer-like symptoms and related pathologies in rodents. MATERIALS AND METHODS: The current investigation involved male SD rats receiving TF (25-100 mg/kg, per oral) consecutively for 21 days in ICV-STZ-treated animals. An in silico study was carried out to explore the possible interaction between TF and NADH dehydrogenase and succinate dehydrogenase. Further, various behavioural (Morris water maze and novel object recognition test), biochemical (oxidants and anti-oxidant markers), activities of mitochondrial enzyme complexes and acetylcholinesterase (AChE), pro-inflammatory (tumor necrosis factor-alpha; TNF-α) levels, and histopathological studies were evaluated in specific brain regions. RESULTS: Rats administered ICV-STZ followed by treatment with TF (25, 50, and 100 mg/kg) for 21 days had significantly better mental performance (reduced escape latency to access platform, extended time spent in target quadrant, and improved differential index) in the Morris water maze test and new object recognition test models when compared to control (ICV-STZ)-treated groups. Further, TF treatment significantly restored redox proportion, anti-oxidant levels, regained mitochondrial capacities, attenuated altered AChE action, levels of TNF-α, and histopathological alterations in certain brain regions in comparison with control. In in silico analysis, TF caused greater interaction with NADH dehydrogenase and succinate dehydrogenase. CONCLUSION: The current work demonstrates the neuroprotective ability of TF in an experimental model with AD-like pathologies. The study further suggests that the neuroprotective impacts of TF may be related to its effects on TNF-α levels, oxidative stress pathways, and mitochondrial complex capabilities.

Development of the multidimensional health perceptions questionnaire in English and Spanish.

PURPOSE: To develop the novel multidimensional health perceptions questionnaire (MHPQ), a self-reported assessment of health perceptions inclusive of (1) individuals beliefs about the causes and consequences of health conditions, benefits and barriers to maintaining and improving health, ability to accomplish health-related goals and control health circumstances, and the role of God and/or spirituality in health and healthcare, (2) anticipated discrimination in the healthcare systems, and (3) trust in healthcare providers and medicine, illustrated in our newly proposed Multidimensional Health Perceptions Conceptual Model. METHODS: We developed an initial MHPQß item set, corresponding to domains of our conceptual model, using a patient-centered outcomes development approach. This include literature review, expert and end-user feedback, translation and language validation (specifically to Latin American Spanish), and cognitive interviewing. RESULTS: The initial 104 items of MHPQß had excellent content validity, with a Content Validity Index of 98.1%. After expert (n = 13) feedback, translation and language validation, and cognitive interviewing among community-dwelling English-speakers (n = 5) and Spanish-speakers (n = 4), the final MHPQß comprised 93 items rated on a five-point agreement scale (1 = Strongly disagree to 5 = Strongly agree), with a reading grade level of 6th grade in English and 8th grade in Spanish. CONCLUSION: The MHPQß is a promising tool to assess individuals' health perceptions. It has excellent content validity and good reading accessibility. Future work will establish the factor structure and final item set of the MHPQ.

An improved method for isolation of RNA from rat femur.

BACKGROUND: RNA isolation from ossified bone is a difficult and time-consuming process which often results in poor recovery of RNA. The yield is limited and might not be suitable for gene quantification studies by real time PCR. METHODOLOGY: The present study demonstrates RNA extraction from rat femur utilizing the silica column along with the trizol reagent. Quality of RNA was assessed by agarose gel analysis and its suitability for real-time PCR analysis was determined by ß-actin Ct values. RESULTS: The RNA isolated using silica columns in conjugation with trizol reagent resulted in higher yield of RNA and purity (A260/280=2.04; yield =1545.73 µg/ml) compared to the trizol method alone (A260/280=1.85; yield =571.2 µg/ml). Ct value of ß actin obtained from RNA isolated by trizol method was higher than the Ct value obtained by trizol in conjugation with the column method (31.41 and 15.41 respectively). CONCLUSION: Combination of trizol along with silica column resulted in better quality and improved yield of RNA suitable for gene quantification by Real time PCR.

Cognitive Decline in Older People with Multiple Sclerosis-A Narrative Review of the Literature.

Several important questions regarding cognitive aging and dementia in older people with multiple sclerosis (PwMS) are the focus of this narrative review: Do older PwMS have worse cognitive decline compared to older people without MS? Can older PwMS develop dementia or other neurodegenerative diseases such as Alzheimer's disease (AD) that may be accelerated due to MS? Are there any potential biomarkers that can help to determine the etiology of cognitive decline in older PwMS? What are the neural and cellular bases of cognitive aging and neurodegeneration in MS? Current evidence suggests that cognitive impairment in MS is distinguishable from that due to other neurodegenerative diseases, although older PwMS may present with accelerated cognitive decline. While dementia is prevalent in PwMS, there is currently no consensus on defining it. Cerebrospinal fluid and imaging biomarkers have the potential to identify disease processes linked to MS and other comorbidities-such as AD and vascular disease-in older PwMS, although more research is required. In conclusion, one should be aware that multiple underlying pathologies can coexist in older PwMS and cause cognitive decline. Future basic and clinical research will need to consider these complex factors to better understand the underlying pathophysiology, and to improve diagnostic accuracy.

Diagnostic Utility of Hippocampal Volumetric Data in a Memory Disorder Clinic Setting.

BACKGROUND: Hippocampal volumetric data are widely used in research but are rarely examined in clinical populations in regard to aiding diagnosis or correlating with objective memory test scores. OBJECTIVE: To replicate and expand on the few prior clinical examinations of the utility of hippocampal volumetric data. We evaluated MRI volumetric data to determine (a) the degree of hippocampal loss across diagnostic groups compared with a cognitively intact group, (b) if total or lateralized hippocampal volumes predict diagnostic group membership, and (c) how total and lateralized volumes correlate with memory tests. METHOD: We retrospectively examined hippocampal volumetric data and memory test scores for 294 individuals referred to a memory clinic. RESULTS: Individuals with mild cognitive impairment or Alzheimer disease had smaller hippocampal volumes compared with cognitively intact individuals. The raw and normalized total and lateralized hippocampal volumes were essentially equal for predicting diagnostic group membership, and notably low hippocampal volumes evidenced greater specificity than sensitivity. All of the volumetric data correlated with the memory test scores, with the total and left hippocampal volumes accounting for the slightly more variance in the diagnostic groups. CONCLUSION: The diagnostic groups exhibited hippocampal volume loss, which can be a potential biomarker for neurodegenerative disease in clinical practice. However, solely using hippocampal volumetric data to predict diagnostic group membership or memory test failure was not supported. While extreme hippocampal volume loss was rare in the cognitively intact group, the sensitivity of these volumetric data suggests a need for supplementation by other tools when making a diagnosis.

Two Unique Mutations in HTRA1-Related Cerebral Small Vessel Disease in North America and Africa and Literature Review.

OBJECTIVE: To describe and compare two cases of North American and African patients who were diagnosed with HTRA1-related cerebral small vessel disease (CSVD) with homozygous and heterozygous mutations, respectively, in the linker domain of the HTRA1 gene. MATERIALS AND METHODS: Case reports and literature review. RESULTS: A 49-year-old man from Mexico presented with recurrent lacunar strokes and memory loss. A 46-year-old woman from Eritrea presented with progressive memory loss. Neither patient had alopecia. MRI of the brain and spine in both patients showed leukoencephalopathy, microbleeds and spondylosis. Microbleeds along the subpial surfaces of the brainstem were only seen in the Mexican man. Genetic sequencing of HTRA1 gene revealed a novel homozygous mutation of p.A173S in the Mexican man supporting cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). A heterozygous mutation of p.V175M was detected in the African woman, which has not been reported in patients of African ethnicity. In reviewing literature, CARASIL patients with mutation in the linker domain are older at neurological symptom onset and more frequently presented with stroke compared to patients with non-linker domain mutations. In patients of HTRA1-CSVD from heterozygous mutations, male is more common. CONCLUSIONS: HTRA1-related CSVD may be seen in patients of non-Asian ethnicity without alopecia. These case reports extend the clinical and radiographic spectrum of HTRA1-related CSVD.

Therapeutic potential of Allium Sativum against the Aß(1-40)-induced oxidative stress and mitochondrial dysfunction in the Wistar rats.

From the early stages of any neurodegenerative-disease mitochondrial functionality has been mortally extricated, though the exact timeline of these events is still unclear, it is likely to represent a progressive neurons-decline and cognitive-functions. Hence strategies suggested by herbal extract to restore mitochondrial functions may be a remedial approach to chronic neurodegenerative disorder like Alzheimer's disease (AD). This research was designed to evaluate if Aß1-40 induced oxidative stress and mitochondrial dysfunction could be inhibited by Allium Sativum (AS) supplementation. AD was induced by a single intra-hippocampal injection of Aß1-40 (5 µg/4 µl), while herbal supplementation was given orally (100, 250, 500 mg/kg body weight, daily) for 3 weeks. Morris water maze was used to assess cognitive function shows deficits in Aß1-40 treated animals, there is no significant alteration in locomotor function as examined by actophotometer. This was accompanied by enhancement in oxidative stress indicating by accentuated ROS and protein carbonyl levels. Concomitantly, decrease in activity of antioxidant enzymes was observed in diseased animals; as expressed by reduced superoxide-dismutase and catalase activity, as well as reduction in GSH levels and impaired mitochondrial functions. Medium dose of AS has been found effective in restoring the memory impairment along with antioxidant levels but high dose is more efficient as observed in the Aß1-40 treated rats. High dose of AS, on the other hand significantly ameliorates the mitochondrial-dysfunction in comparison to medium dose. Taken together, the findings reveal that AS reverses Aß1-40 induced brain alteration, it could be an efficient clinical mitigation action against AD growth.

Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis.

The synergism between estrogen and histone tail acetylation-mediated memory formation is not clearly understood. Here, we attempt to study the altered histone acetylation homeostasis mediated changes in cognition following ovariectomy and evaluate the protective effect of quercetin. A significant reduction in estradiol levels with subsequent depletion in spatial memory and learning functions assessed by Morris water maze, novel object recognition test and elevated plus maze was observed in ovariectomized (OVX) mice. Correspondingly, a significant decline in neuroplasticity markers like brain-derived neurotrophic factor (BDNF), synaptophysin (SYP) and postsynaptic density-95 (PSD-95) was observed in cortex and hippocampus of OVX animals. Notably, histone acetyltransferase (HAT)/histone deacetylase (HDAC) balance was significantly disrupted in cortex and hippocampus of OVX mice. Lowered extracellular signal regulated kinases (ERK) and cAMP response element binding protein activation observed in OVX brain regions might account for HAT/HDAC imbalance. Altered HAT/HDAC homeostasis results in lowered histone 3 acetylation in OVX brain that suppressed transcriptional activation of neuroplasticity-related genes. Quercetin supplementation to OVX mice for 4 weeks was able to ameliorate cognitive impairment by restoring HAT/HDAC homeostasis through ERK activation and reversing alterations in neuroplasticity markers in cortex and hippocampus of OVX mice. Taken together, our results suggest that quercetin alleviates ovariectomy-induced cognitive decline by modulating histone acetylation homeostasis.

Lack of association between lysyl oxidase-like 1 polymorphism in pseudoexfoliation syndrome and pseudoexfoliation glaucoma in North Indian population.

INTRODUCTION: Pseudoexfoliation syndrome is commonly associated with pseudoexfoliation glaucoma. The two nonsynonymous single-nucleotide polymorphisms rs1048661 (R141L) and rs3825942 (G153D) within exon 1 of LOXL1 gene have been found to confer risk of pseudoexfoliation syndrome and pseudoexfoliation glaucoma in different geographical populations. This study aims to find association between two nonsynonymous single-nucleotide polymorphisms with pseudoexfoliation syndrome and pseudoexfoliation glaucoma in North Indian population. METHODS: North Indian subjects clinically diagnosed with pseudoexfoliation syndrome/pseudoexfoliation glaucoma and normal age-matched control were enrolled in the study. Genomic DNA was extracted and the two single-nucleotide polymorphisms of LOXL1 gene were genotyped by polymerase chain reaction and sequencing. The association between single-nucleotide polymorphisms with pseudoexfoliation syndrome/pseudoexfoliation glaucoma was evaluated by chi-square test. RESULTS: A total of 30 pseudoexfoliation glaucoma, 27 pseudoexfoliation syndrome and 61 control subjects were enrolled in the study. Patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma did not show any genetic association with either single-nucleotide polymorphism rs1048661 or rs3825942. CONCLUSION: The study shows lack of association between LOXL1 single-nucleotide polymorphisms and pseudoexfoliation in North Indian population.

Resveratrol restores the level of key inflammatory cytokines and RANKL/OPG ratio in the femur of rat osteoporosis model.

Resveratrol's effect on bone mineral density (BMD) and expression of cytokines in ovariectomized rats (postmenopausal osteoporosis model) was studied. The study was conducted on 3-month-old Sprague-Dawley rats that were (a) sham-operated, (b) ovariectomized, (c) ovariectomized and treated with ß-estradiol (487.5 µg/kg weight/day), and (d) ovariectomized and treated with resveratrol (625 µg/Kg body weight/day). The treatment was for 4 weeks. After sacrifice BMD and gene expression (RANKL, OPG, IL-23, and IL-17A, IL-1ß, and TNFα) were measured in tibia and femur respectively. Resveratrol could restore RANKL/OPG ratio, slightly increase BMD, and moderately but significantly reduce IL-23, IL-17A, IL-1ß, and TNF-α cytokine expression levels.

Reduced expressions of calmodulin genes and protein and reduced ability of calmodulin to activate plasma membrane Ca(2+)-ATPase in the brain of protein undernourished rats: modulatory roles of selenium and zinc supplementation.

The roles of protein undernutrition as well as selenium (Se) and zinc (Zn) supplementation on the ability of calmodulin (CaM) to activate erythrocyte ghost membrane (EGM) Ca(2+)-ATPase and the calmodulin genes and protein expressions in rat's cortex and cerebellum were investigated. Rats on adequate protein diet and protein-undernourished (PU) rats were fed with diet containing 16% and 5% casein, respectively, for a period of 10 weeks. The rats were then supplemented with Se and Zn at a concentration of 0.15 and 227 mg l(-1), respectively, in drinking water for 3 weeks. The results obtained from the study showed significant reductions in synaptosomal plasma membrane Ca(2+)-ATPase (PMCA) activity, Ca(2+)/CaM activated EGM Ca(2+) ATPase activity and calmodulin genes and protein expressions in PU rats. Se or Zn supplementation improved the ability of Ca(2+)/CaM to activate EGM Ca(2+)-ATPase and protein expressions. Se or Zn supplementation improved gene expression in the cerebellum but not in the cortex. Also, the activity of PMCA was significantly improved by Zn. In conclusion, it is postulated that Se and Zn might be beneficial antioxidants in protecting against neuronal dysfunction resulting from reduced level of calmodulin such as present in protein undernutrition.

S-nitrosoglutathione prevents blood-brain barrier disruption associated with increased matrix metalloproteinase-9 activity in experimental diabetes.

Hyperglycemia is known to induce microvascular complications, thereby altering blood-brain barrier (BBB) permeability. This study investigated the role of matrix metalloproteinases (MMPs) and their endogenous inhibitors in increased BBB permeability and evaluated the protective effect of S-nitrosoglutathione (GSNO) in diabetes. Diabetes was induced in mice by intraperitoneal injection of streptozotocin (40 mg/kg body weight) for 5 days and GSNO was administered orally (100 µg/kg body weight) daily for 8 weeks after the induction of diabetes. A significant decline in cognitive functions was observed in diabetic mice assessed by Morris water maze test. Increased permeability to different molecular size tracers accompanied by edema and ion imbalance was observed in cortex and hippocampus of diabetic mice. Furthermore, activity of both pro and active MMP-9 was found to be significantly elevated in diabetic animals. Increased in situ gelatinase activity was observed in tissue sections and isolated microvessels from diabetic mice brain. The increase in activity of MMP-9 was attributed to increased mRNA and protein expression in diabetic mice. In addition, a significant decrease in mRNA and protein expression of tissue inhibitor of matrix metalloproteinase-1 was also observed in diabetic animals. However, GSNO supplementation to diabetic animals was able to abridge MMP-9 activation as well as tissue inhibitor of matrix metalloproteinase-1 levels, restoring BBB integrity and also improving learning and memory. Our findings clearly suggest that GSNO could prevent hyperglycemia-induced disruption of BBB by suppressing MMP-9 activity.

Coenzyme Q10 treatment ameliorates cognitive deficits by modulating mitochondrial functions in surgically induced menopause.

The mechanisms associated with cognitive decline in post-menopausal state driven by loss of ovarian function and reduced estrogen levels are not well understood. The aim of the present study is to investigate the role of mitochondrial dysfunctions in cognitive impairment in post-menopausal state and to evaluate the protective effect of Coenzyme Q10 (CoQ10). A significant decline in cognitive functions was observed in mice after four weeks of ovariectomy as assessed by morris water maze and elevated plus maze. Administration of CoQ10 (10 mg/kg body weight, orally) daily for 4 weeks was found to reverse cognitive deficits observed in ovariectomized (Ovx) mice. The activity of mitochondrial electron transport chain components; NADH: cytochrome c reductase, succinate dehydrogenase and cytochrome c oxidase was significantly reduced in the brain of Ovx mice. This was accompanied by higher levels of ROS, protein carbonyls, lipid peroxidation, mitochondrial swelling and reduced activity of aconitase. The levels of GSH were observed to be significantly lowered resulting in reduced redox ratio (GSH/GSSG) in brain of Ovx mice. Activities of antioxidant enzymes; superoxide dismutase and catalase were also found to be reduced in brain of Ovx animals. CoQ10 supplementation to Ovx mice mitigated the mitochondrial dysfunctions and oxidative stress. Thus, the data indicates that CoQ10 improves cognitive decline in post-menopausal state by modulating mitochondrial functions and oxidative stress.

Attenuation of cellular antioxidant defense mechanisms in kidney of rats intoxicated with carbofuran.

Carbofuran, an anticholinestrase carbamate, is commonly used as an insecticide. Its toxic effect on kidney is less established. The present study was designed to investigate the effect of carbofuran on kidneys and to understand the mechanism involved in its nephrotoxicity. Male Wistar rats were divided into two groups of eight animals each; control animals received sunflower oil (vehicle) and carbofuran exposed animals were treated with carbofuran (1 mg/kg body weight) orally for 28 days. At the end of the treatment, significant increase was observed in urea and creatinine levels in serum along with the inhibition of acetylcholinesterase, suggesting nephrotoxicity. The antioxidant defense system of animals treated with carbofuran was altered in terms of increased lipid peroxidation, reduced glutathione, and total thiols and decreased activity of antioxidant enzymes (superoxide dismutase and catalase). The results indicate that carbofuran is nephrotoxic and increased oxidative stress appears to be involved in its nephrotoxic effects.