- Donepezil Monotherapy for Neurocognitive Deficits and Psychobehavioral Disinhibition in an Adolescent Posttraumatic Brain Injury. [Journal Article]
- AJAm J Ther 2017 May 17
- Pharmacogenetic studies in Alzheimer disease. [Journal Article]
- NNeurologia 2018 Jun 10
- CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as aging.
- The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges. [Journal Article]
- JPJ Psychopharmacol 2018 Jun 01; :269881118779383
- Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to ex...
Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens. Here we assessed baseline performance as well as multimodal disease-relevant manipulations in mice. Mice were trained to discriminate between the locations of two images where the degree of separation impacted performance. Administration of putative pro-cognitive agents was unable to improve performance at narrow separation. Furthermore, a range of disease-relevant manipulations were characterized to assess whether performance could be impaired and restored. Pertinent to the cholinergic loss in AD, scopolamine (0.1 mg/kg) produced a disruption in LDR, which was attenuated by donepezil (1 mg/kg). Consistent with NMDA hypofunction in cognitive impairment associated with SZ, MK-801 (0.1 mg/kg) also disrupted performance; however, this deficit was not modified by rolipram. Microdeletion of genes associated with SZ (22q11) resulted in impaired performance, which was restored by rolipram (0.032 mg/kg). Since aging and inflammation affect cognition and are risk factors for AD, these aspects were also evaluated. Aged mice were slower to acquire the task than young mice and did not reach the same level of performance. A systemic inflammatory challenge (lipopolysaccharide (LPS), 1 mg/kg) produced prolonged (7 days) deficits in the LDR task. These data suggest that LDR task is a valuable platform for evaluating disease-relevant deficits in pattern separation and offers potential for identifying novel therapies.
- Strategies for Continued Successful Treatment in Patients with Alzheimer's Disease: An Overview of Switching Between Pharmacological Agents. [Journal Article]
- CACurr Alzheimer Res 2018 Jun 12
- CONCLUSIONS: The findings of this review indicate that dose up-titration and switching between ChEIs may help to improve response to ChEI treatment and also address issue such as lack/loss of efficacy or safety/tolerability in patients with AD. However, well-designed studies are needed to provide robust evidences.
- Sex and Gender Differences in the Brain Cholinergic System and in the Response to Therapy of Alzheimer Disease with Cholinesterase Inhibitors. [Journal Article]
- CACurr Alzheimer Res 2018 Jun 12
- This review has two aims. First, to examine whether or not sex and gender may influence the brain cholinergic system in animals and in humans. Second, to examine the available evidence of sexually di...
This review has two aims. First, to examine whether or not sex and gender may influence the brain cholinergic system in animals and in humans. Second, to examine the available evidence of sexually dimorphic response to the therapeutic and toxic effects of cholinesterase inhibitors. Animal research reveals no marked difference in the general morphology of the brain cholinergic system but subtle functional gender differences have been reported. In humans, gender differences in nucleus basalis of Meynert (NBM) exist. In animals, some cholinergic neurons express estrogen alpha receptors in females and androgens in males. It is known that sex hormones exert trophic effects on the cholinergic system. Females show higher frontal cortex cholinergic activity whereas males have higher activity in the hippocampus. Gender differences in the pharmacological effects result in higher sensitivity to the toxic effects of organophosphate cholinesterase inhibitors in males. A stronger and more selective benefit of ChEI treatment in AD has been reported in men by several authors. Sex and estrogen receptor phenotype may both influence the response to donepezil and rivastigmine. Hence, aged male and female individuals might respond differently to ChEI due to either sex-specific differences in structures and function of the cholinergic system, pharmacokinetics, memory function or in the way aging or AD affects these processes.
- Chronic Administration of Piperine Attenuates Behavioural, Biochemical and Histological Alterations induced by Intracerebroventricular Streptozotocin in Rats. [Journal Article]
- BCBasic Clin Pharmacol Toxicol 2018 Jun 11
- Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Piperine is the major bio-active component of pepper. The aim of this study was to determine potential effects of...
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Piperine is the major bio-active component of pepper. The aim of this study was to determine potential effects of chronic treatment with piperine on underlying biochemical, histological and behavioral changes following intracerebroventricular streptozotocin injection. Adult male Wistar rats, weighing 200-220g, were randomly assigned into 9 groups. In order to provide an animal model of the AD, streptozotocin (STZ) was bilaterally injected (3 mg/kg) into the lateral ventricles (ICV) twice on days 1 and 3. The rats were given piperine at various doses ranging from 2.5, 5, 10 and 20 mg/kg for 28 consecutive days, starting from 7 days after the second STZ injection. Morris water maze test was used to evaluate the spatial memory. One day after completion of the behavioural study, animals were decapitated and the bilateral hippocampi dissected for biochemical and histolopathological studies. Results showed that markedly spatial memory impairment is well correlated with increment of lipid peroxidation and decline in the antioxidant status and neuronal loss of the hippocampus in the STZ-injected rats. Interestingly, results showed that the cytoarchitecture of the hippocampal sub-regions retained their integrity during chronic treatment with piperine, and the behavioural test performed revealed that chronic piperine administration for 28 days showed improvements in cognitive performance and attenuated oxidative stress in the hippocampus tissue following ICV-STZ injection in a dose-dependent manner. Moreover, piperine supplementation at a physiologically relevant dose (5mg/kg/day) successfully restored antioxidant status and produced dose-dependent effects by promotion of neuronal survival rate in the hippocampus, which is comparable to that positive beneficial effects observed in donepezil (1 mg/kg/day, i.p) treated group. These findings suggest that long-term piperine supplementation improved STZ-induced cognitive impairment and enhanced the same survival rate of hippocampal neurons as in group receiving donepezil via ROS-related redox regulation and antioxidant defence mechanism potentiation in the hippocampus. This article is protected by copyright. All rights reserved.
- Rational design of carbamate-based dual binding site and central AChE inhibitors by a "biooxidisable" prodrug approach: Synthesis, in vitro evaluation and docking studies. [Journal Article]
- EJEur J Med Chem 2018 Jun 01; 155:171-182
- Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent...
Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.
- FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of vascular dementia. [Journal Article]
- BBBehav Brain Res 2018 Jun 07
- Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been de...
Vascular dementia (VD) is a heterogeneous group of brain disorders in which cognitive impairment is attributed to cerebrovascular pathologies. Autophagy, a self-cannibalization mechanism, has been demonstrated to be involved in VD progression. Molecular hydrogen is known for its powerful anti-oxidative, anti-apoptotic, and anti-inflammatory activities, and it is also involved in autophagy. However, the effects of hydrogen on VD remain unclear. The current study found that hydrogen-rich water (HRW) significantly alleviated spatial learning and memory impairments. Similar to donepezil treatment, HRW also inhibited neuron loss and shrinkage in the hippocampal CA1 region. In addition, we found that HRW significantly increased the Bcl-2/Bax expression ratio and decreased cleaved caspase-3 expression levels in the hippocampus of VD rats. Moreover, electron microscopy revealed that HRW decreased the number of autophagosomes. We also observed that HRW reduced the increased ratio of LC3-II/I and Beclin 1 expression and saliently upregulated p62 expression. Furthermore, FoxO1 (a major mediator of autophagy regulation) and Atg7 levels were apparently decreased in the hippocampus of HRW-treated bilateral common carotid artery occlusion (2VO) rats. Taken together, these data show that molecular hydrogen exerts beneficial effects on cognitive impairment induced by chronic cerebral hypoperfusion. FoxO1-mediated autophagy plays an important role in the neuroprotective effects of hydrogen in a rat model of VD. Furthermore, the present findings highlight that HRW should be further investigated as a new therapeutic strategy for VD treatment in the future.
- Mechanisms and Therapy for Cancer Metastasis to the Brain. [Review]
- FOFront Oncol 2018; 8:161
- Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symp...
Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60-70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a "piecemeal" resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other "druggable" alterations seen in up to 5% of NSCLC patients are the rearrangements of the "anaplastic lymphoma kinase" gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).
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- Comparative Evaluation of Prosopis cineraria (L.) Druce and Its ZnO Nanoparticles on Scopolamine Induced Amnesia. [Journal Article]
- FPFront Pharmacol 2018; 9:549
- Over recent years, utilization of green synthesized nanomaterials has been widely growing on human body because of its special properties. With the increasing acceptance of nanoparticle approach for ...
Over recent years, utilization of green synthesized nanomaterials has been widely growing on human body because of its special properties. With the increasing acceptance of nanoparticle approach for various clinical treatments, the biosafety and toxicological effects on the vital organs such as central nervous system, have received more concern. Main focus of this study was to evaluate acute exposure of n-butanol fraction of Prosopis cineraria (L.) Druce hydroethanolic extract (BuPC) and green synthesized zinc oxide nanoparticles of BuPC (ZnOPC) on spatial cognition behavior, and to assess underlying mechanism by estimation of enzymatic antioxidative status along with acetylcholinesterase (AChE) activity in mice brain. Strongest in vitro antioxidant and AChE inhibitory activity exhibiting fraction, BuPC, was examined for inhibition kinetic study by Lineweaver-Burk and Dixon plots. BuPC was further used for fabrication ZnOPC and characterized by UV-visible spectroscopy, Fourier Transform Infrared (FTIR), Field Emission Scanning Electron Microscopy (FESEM), Energy Dispersive X ray (EDX), and Dynamic Light Scattering (DLS) analysis. Old male swiss albino mice were randomly divided into seven groups and treated for 21 days. Subsequently spatial memory was determined by two behavioral models [Elevated plus maze (EPM) and Hebbs William maze (HWM)] and supernatant of brain homogenate was analyzed for enzymatic antioxidant level and AChE inhibitory activity. Zinc content of blood plasma and brain was estimated. Results showed prolonged transfer latency (TL) and time taken to reach reward chamber (TRC) by scopolamine was not ameliorated by the ZnOPC group, whereas BuPC group showed significant reduction in scopolamine induced increase in TL and TRC compared to control and scopolamine treated groups. ZnOPC alleviated enzymatic antioxidant activity and AChE as compared to donepezil and BuPC treated groups. Study concludes that ZnOPC attenuated spatial learning and memory by increase in oxidative stress and decrease in AChE activity at both dose levels. Our results suggest that BuPC exhibited a strong neuroprotective effect on cognitive deficit mice and it may be employed as a strong substance for the treatment of dementia whereas the green synthesized ZnOPC was not proficient to reverse the memory impairment induced by scopolamine.