Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Wu L
PROVIDER: S-EPMC8208785 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND AND PURPOSE:Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH:Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS:MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS:MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.
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Project description:It has been shown previously that a novel tetrapeptide, Arg-Leu-Tyr-Glu (RLYE), derived from human plasminogen inhibits vascular endothelial growth factor (VEGF)-induced angiogenesis, suppresses choroidal neovascularization in mice by an inhibition of VEGF receptor-2 (VEGFR-2) specific signaling pathway. In this study, we report that a modified tetrapeptide (Ac-RLYE) showed improved anti-choroidal neovascularization (CNV) efficacy in a number of animal models of neovascular age-related macular degeneration (AMD) which include rat, rabbit, and minipig. The preventive and therapeutic in vivo efficacy of Ac-RLYE via following intravitreal administration was determined to be either similar or superior to that of ranibizumab and aflibercept. Assessment of the intraocular pharmacokinetic and toxicokinetic properties of Ac-RLYE in rabbits demonstrated that it rapidly reached the retina with minimal systemic exposure after a single intravitreal dose, and it did not accumulate in plasma during repetitive dosing (bi-weekly for 14 weeks). Our results suggested that Ac-RLYE has a great potential for an alternative therapeutics for neovascular (wet) AMD. Since the amino acids in human VEGFR-2 targeted by Ac-RLYE are conserved among the animals employed in this study, the therapeutic efficacies of Ac-RLYE evaluated in those animals are predicted to be observed in human patients suffering from retinal degenerative diseases.
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Project description:Previous studies on repetitive transcranial magnetic stimulation (rTMS) suggested potential neurorestorative properties in Alzheimer's disease (AD). This study aimed to investigate therapeutic effects of rTMS on an AD mouse model at high and low frequencies. The subject mice were allocated into the AD model group (AD induced by intracerebroventricular amyloid beta 42 oligomer [Aβ42] injection) and the saline-injected control group. Each group was subdivided according to rTMS treatment: high frequency (20 Hz), low frequency (1 Hz), and not rTMS-treated. Behavioural assessments with Y-maze test and novel object recognition task were performed; the results indicated cognition recovery by both the frequencies of rTMS after treatment in the AD model (Ps < 0.01). Tendency of further effects by high frequency compared to low frequency rTMS was also shown in Y-maze test. Neurotransmitter assay showed increment in dopamine concentration and upregulation of dopamine-receptor 4 (DR4) by rTMS in AD mice with higher response by high frequency stimulation (Ps < 0.05). Only high-frequency rTMS induced an elevation of brain-derived neurotrophic factor (BDNF) levels and enhanced the expression of Nestin and NeuN in the brain tissue (Ps < 0.05). Under in vitro conditions, Aβ42 incubated mouse hippocampal cell showed an increase in dopamine levels and BDNF by application of high-frequency rTMS treatment. In conclusion, rTMS might have a potential therapeutic effect on AD, and it seems to be related with dopaminergic activation. High frequency of stimulation seems to induce higher efficacy than that induced by low frequency, with elevated expressions of DR4 gene and neurogenic proteins.
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Project description:Systemic lupus erythematosus is a chronic autoimmune disease frequently affecting the kidney. Renal involvement is characterized by glomerular immune complex deposits and proliferative glomerulonephritis progressing to glomerulosclerosis and kidney failure. The development of systemic lupus erythematosus is regulated genetically, and lupus susceptibility genes have been linked to immune hyper-responsiveness and loss of immune regulation. In addition to the systemic immune defects, recent studies in animal models show that susceptibility to lupus nephritis is influenced by intrinsic renal factors. Thus, renal cell responses to immune-mediated glomerular injury determine disease outcome. This supports the idea that future treatments for lupus nephritis need to focus on regulating end-organ responses. The feasibility of this approach has been shown in animal models of kidney disease. For more than 50 years, the emphasis in management of lupus nephritis has been suppression of autoimmune responses and systemic control of inflammation. This review describes recently developed targeted drug delivery technologies and potential targets that can regulate glomerular cell responses, offering a novel therapeutic approach for lupus nephritis.
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Project description:BACKGROUND:Agitation in Alzheimer's disease (AD) is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD. METHODS AND FINDINGS:We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI). Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI), Clinical Global Impression Change (CGI-C), Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p?=?0.26); or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p?=?0.012) and 12 (-9.6; -15.0 to -4.3 p?=?0.0005). Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD. CONCLUSIONS:Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms. TRIAL REGISTRATION:ClinicalTrials.gov NCT00371059. TRIAL REGISTRATION:International Standard Randomised Controlled Trial 24953404.
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Project description:The dominant gain-of-function polyglutamine repeat diseases, in which the initiating mutation is known, allow development of models that recapitulate many aspects of human disease. To the extent that pathology is a consequence of disrupted fundamental cellular activities, one can effectively study strategies to ameliorate or protect against these cellular insults. Model organisms allow one to identify pathways that affect disease onset and progression, to test and screen for pharmacological agents that affect pathogenic processes, and to validate potential targets genetically as well as pharmacologically. Here, we describe polyglutamine repeat diseases that have been modeled in a variety of organisms, including worms, flies, mice, and non-human primates, and discuss examples of how they have broadened the therapeutic landscape.
| S-EPMC2658038 | biostudies-literature
Project description:Age-progressive neurodegenerative pathologies, including Alzheimer's disease (AD), are distinguished and diagnosed by disease-specific components of intra- or extra-cellular aggregates. Increasing evidence suggests that neuroinflammation promotes protein aggregation, and is involved in the etiology of neurological diseases. We synthesized and tested analogs of the naturally occurring tubulin-binding compound, combretastatin A-4. One such analog, PNR502, markedly reduced the quantity of Alzheimer-associated amyloid aggregates in the BRI-Aβ1-42 mouse model of AD, while blunting the ability of the pro-inflammatory cytokine IL-1β to raise levels of amyloid plaque and its protein precursors in a neuronal cell-culture model. In transgenic Caenorhabditis elegans (C. elegans) strains that express human Aβ1-42 in muscle or neurons, PNR502 rescued Aβ-induced disruption of motility (3.8-fold, P < 0.0001) or chemotaxis (1.8-fold, P < 0.05), respectively. Moreover, in C. elegans with neuronal expression of Aβ1-42, a single day of PNR502 exposure reverses the chemotaxis deficit by 54% (P < 0.01), actually exceeding the protection from longer exposure. Moreover, continuous PNR502 treatment extends nematode lifespan 23% (P ≤ 0.001). Given that PNR502 can slow, prevent, or reverse Alzheimer-like protein aggregation in human-cell-culture and animal models, and that its principal predicted and observed binding targets are proteins previously implicated in Alzheimer's, we propose that PNR502 has therapeutic potential to inhibit cerebral Aβ1-42 aggregation and prevent or reverse neurodegeneration.
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Project description:When mimicking epileptic processes in a laboratory setting, it is important to understand the differences between experimental models of seizures and epilepsy. Because human epilepsy is defined by the appearance of multiple spontaneous recurrent seizures, the induction of a single acute seizure without recurrence does not constitute an adequate epilepsy model. Animal models of epilepsy might be useful for various tasks. They allow for the investigation of pathophysiological mechanisms of the disease, the evaluation, or the development of new antiepileptic treatments, and the study of the consequences of recurrent seizures and neurological and psychiatric comorbidities. Although clinical relevance is always an issue, the development of models of pediatric epilepsies is particularly challenging due to the existence of several key differences in the dynamics of human and rodent brain maturation. Another important consideration in modeling pediatric epilepsy is that "children are not little adults," and therefore a mere application of models of adult epilepsies to the immature specimens is irrelevant. Herein, we review the models of pediatric epilepsy. First, we illustrate the differences between models of pediatric epilepsy and models of the adulthood consequences of a precipitating insult in early life. Next, we focus on new animal models of specific forms of epilepsies that occur in the developing brain. We conclude by emphasizing the deficiencies in the existing animal models and the need for several new models.
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Project description:The most common animal models currently used for Alzheimer disease (AD) research are transgenic mice that express a mutant form of human Abeta precursor protein (APP) and/or some of the enzymes implicated in their metabolic processing. However, these transgenic mice carry their own APP and APP-processing enzymes, which may interfere in the production of different amyloid-beta (Abeta) peptides encoded by the human transgenes. Additionally, the genetic backgrounds of the different transgenic mice are a possible confounding factor with regard to crucial aspects of AD that they may (or may not) reproduce. Thus, although the usefulness of transgenic mice is undisputed, we hypothesized that additional relevant information on the physiopathology of AD could be obtained from other natural non-transgenic models. We have analyzed the chick embryo and the dog, which may be better experimental models because their enzymatic machinery for processing APP is almost identical to that of humans. The chick embryo is extremely easy to access and manipulate. It could be an advantageous natural model in which to study the cell biology and developmental function of APP and a potential assay system for drugs that regulate APP processing. The dog suffers from an age-related syndrome of cognitive dysfunction that naturally reproduces key aspects of AD including Abeta cortical pathology, neuronal degeneration and learning and memory disabilities. However, dense core neuritic plaques and neurofibrillary tangles have not been consistently demonstrated in the dog. Thus, these species may be natural models with which to study the biology of AD, and could also serve as assay systems for Abeta-targeted drugs or new therapeutic strategies against this devastating disease.
| S-EPMC2825666 | biostudies-literature
Project description:In Alzheimer's disease (AD), vascular pathology may interact with neurodegeneration and thus aggravate cognitive decline. As the relationship between these two processes is poorly understood, research has been increasingly focused on understanding the link between cerebrovascular alterations and AD. This has at last been spurred by the engineering of transgenic animals, which display pathological features of AD and develop cerebral amyloid angiopathy to various degrees. Transgenic models are versatile for investigating the role of amyloid deposition and vascular dysfunction, and for evaluating novel therapeutic concepts. In addition, research has benefited from the development of novel imaging techniques, which are capable of characterizing vascular pathology in vivo. They provide vascular structural read-outs and have the ability to assess the functional consequences of vascular dysfunction as well as to visualize and monitor the molecular processes underlying these pathological alterations. This article focusses on recent in vivo small animal imaging studies addressing vascular aspects related to AD. With the technical advances of imaging modalities such as magnetic resonance, nuclear and microscopic imaging, molecular, functional and structural information related to vascular pathology can now be visualized in vivo in small rodents. Imaging vascular and parenchymal amyloid-β (Aβ) deposition as well as Aβ transport pathways have been shown to be useful to characterize their dynamics and to elucidate their role in the development of cerebral amyloid angiopathy and AD. Structural and functional imaging read-outs have been employed to describe the deleterious affects of Aβ on vessel morphology, hemodynamics and vascular integrity. More recent imaging studies have also addressed how inflammatory processes partake in the pathogenesis of the disease. Moreover, imaging can be pivotal in the search for novel therapies targeting the vasculature.
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