Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.
"In AD, increased expression of glial fibrillary acidic protein (GFAP) is typically observed in immunohistochemical studies of post-mortem brain tissue, indicating an increased number of reactive astrocytes , with GFAP-positive astrocytes noted at the margins of amyloid deposits . Though the astrocytic network is thought to exert a neuroprotective role via the sequestration/degradation of Aβ [101-105], its involvement is likewise believed to extend in deleterious directions, including the amplification of cortical amyloid deposition via propagation of intercellular calcium waves . "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiological process, where the accumulation of amyloid-beta (Abeta) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addition to Abeta pathology, various lines of research have implicated neuroinflammation as an important participant in AD pathophysiology. Currently, neuroinflammation can be measured in vivo using positron emission tomography (PET) with ligands targeting diverse biological processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiological studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clinical trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathology. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clinical trials using NSAIDs. In this review, we address the biological basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compounds, and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.
Journal of Neuroinflammation 07/2014; 11(1):120. DOI:10.1186/1742-2094-11-120 · 5.41 Impact Factor
"Epidemiological studies have suggested that long-term use of NSAIDs may protect against AD.12,13,43 However, the hypothesis that IndOH slows the incidence and progression of AD remains controversial.12,13,43 The presence of the BBB impedes effective treatment of many brain diseases, because large doses are required to reach the minimum effective concentration in the brain, thereby negatively affecting drug efficacy and tolerance.44 "
[Show abstract][Hide abstract] ABSTRACT: Neuroinflammation, characterized by the accumulation of activated microglia and reactive astrocytes, is believed to modulate the development and/or progression of Alzheimer's disease (AD). Epidemiological studies suggesting that nonsteroidal anti-inflammatory drugs decrease the risk of developing AD have encouraged further studies elucidating the role of inflammation in AD. Nanoparticles have become an important focus of neurotherapeutic research because they are an especially effective form of drug delivery. Here, we investigate the potential protective effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNCs) against cell damage and neuroinflammation induced by amyloid beta (Aβ)1-42 in AD models. Our results show that IndOH-LNCs attenuated Aβ-induced cell death and were able to block the neuroinflammation triggered by Aβ1-42 in organotypic hippocampal cultures. Additionally, IndOH-LNC treatment was able to increase interleukin-10 release and decrease glial activation and c-jun N-terminal kinase phosphorylation. As a model of Aβ-induced neurotoxicity in vivo, animals received a single intracerebroventricular injection of Aβ1-42 (1 nmol/site), and 1 day after Aβ1-42 infusion, they were administered either free IndOH or IndOH-LNCs (1 mg/kg, intraperitoneally) for 14 days. Only the treatment with IndOH-LNCs significantly attenuated the impairment of this behavior triggered by intracerebroventricular injection of Aβ1-42. Further, treatment with IndOH-LNCs was able to block the decreased synaptophysin levels induced by Aβ1-42 and suppress glial and microglial activation. These findings might be explained by the increase of IndOH concentration in brain tissue attained using drug-loaded lipid-core NCs. All these findings support the idea that blockage of neuroinflammation triggered by Aβ is involved in the neuroprotective effects of IndOH-LNCs. These data provide strong evidence that IndOH-LNC treatment may represent a promising approach for treating AD.
International Journal of Nanomedicine 09/2012; 7:4927-42. DOI:10.2147/IJN.S35333 · 4.38 Impact Factor
"Moreover, transgenic mice over-expressing COX-2 develop an agedependent memory deficit that suggests a contribution to neurodegeneration that may affect the progression of AD. In addition to microgliosis, higher COX-1 and COX-2 protein levels are observed in post-mortem AD brains than in agematched , non-demented controls   . "
[Show abstract][Hide abstract] ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of often chemically unrelated compounds with some common therapeutic actions and side effects. They have potent anti-inflammatory, analgesic and antipyretic activity, and are among the most widely used drugs worldwide. It is generally thought that one of their main mechanisms of action is the inhibition of cyclo-oxygenase (COX), the enzyme responsible for biosynthesing the prostaglandins and thromboxane. NSAIDs are also associated with an increased risk of adverse gastrointestinal, renal and cardiovascular effects. This review describes the clinical pharmacology of NSAIDs, their classification, molecular mechanisms of action and adverse effects, including their possible contribution to neuro-inflammation and carcinogenesis, as well as some recent developments aimed at designing effective anti-inflammatory agents with improved safety and tolerability profiles.
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Cu rrent Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) 08/2012; 11(1):52-64. DOI:10.2174/187152312803476255
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