Protection of rat primary hippocampal cultures from Aβ cytotoxicity by pro-inflammatory molecules is mediated by astrocytes

Ramı́rez, Galo; Toro, Rodrigo; Döbeli, Heinz; Bernhardi, Rommy von

doi:10.1016/j.nbd.2005.01.007

Cited by 57 publications

(47 citation statements)

References 74 publications

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“…The study proposes a novel cellular mechanism underlying the beneficial effects of melatonin against degeneration of the central nervous system. The significance of our findings is that, in addition to the beneficial effects of providing direct antioxidant protection to neurons as reported, melatonin may also provide neuroprotection through the suppression of glial reactivity and the promotion of the antioxidant defense system of glial cells [29,[79][80][81][82][83][84][85] . Melatonin treatment exerted neuroprotective effects against injury by promoting the survival of both glial cells and neurons.…”

Section: Melatonin Reduces Aβ-induced Apoptosis In Pheochromocytoma (supporting

confidence: 53%

“…The precise mechanisms behind the effects of antiapoptotic drugs in astrocytes remain unknown. Advances in our knowledge of the molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders [29,[78][79][80][81][82][83][84][85] . The study proposes a novel cellular mechanism underlying the beneficial effects of melatonin against degeneration of the central nervous system.…”

Section: Melatonin Reduces Aβ-induced Apoptosis In Pheochromocytoma (mentioning

confidence: 99%

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Beneficial effects of melatonin in experimental models of Alzheimer disease1

Cheng

Zhao

Zhang

et al. 2006

Acta Pharmacologica Sinica

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Alzheimer's disease (AD), a progressive degenerative disorder, is characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. It has been shown that melatonin is a potent antioxidant and free radical scavenger. Additionally, melatonin stimulates several antioxidative enzymes and improves mitochondrial energy metabolism. These findings led us to study amyloid precursor protein transgenic mice, ovariectomized rats, and pheochromocytoma and astroglioma cell lines, to observe whether melatonin had any effect on Alzheimer's symptoms or pathological changes. We found that melatonin had many beneficial effects in experimental models of AD, including improvement of cognitive function, anti-oxidative injury, anti-apoptosis, inhibition of β-amyloid (Aβ) deposition and Aβ fiber formation. Several groups have shown that melatonin has an inhibitory effect on tau protein hyperphosphorylation. These actions may potentially slow down or stop the progression of dementia.

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Section: Melatonin Reduces Aβ-induced Apoptosis In Pheochromocytoma (supporting

confidence: 53%

Section: Melatonin Reduces Aβ-induced Apoptosis In Pheochromocytoma (mentioning

confidence: 99%

Beneficial effects of melatonin in experimental models of Alzheimer disease1

Cheng

Zhao

Zhang

et al. 2006

Acta Pharmacologica Sinica

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“…Protection depends on the presence of astrocytes [8] . Astrocytes decrease reactivity of microglial cells to A ␤ , decrease NO secretion and prevent apoptosis in hippocampal cultures exposed to A ␤ and pro-inflammatory molecules [7,8] .…”

Section: Discussionmentioning

confidence: 99%

“…They also play a neuroprotective role by modulating microglial cell activity and decreasing their cytotoxicity [7,8] . Production of soluble mediators such as TGF-␤ by activated astrocytes and hippocampal cells has been shown to modulate reactive oxygen species and NO production by microglial cells [9] .…”

mentioning

confidence: 99%

Modulation by Astrocytes of Microglial Cell-Mediated Neuroinflammation: Effect on the Activation of Microglial Signaling Pathways

Tichauer

Saud

Bernhardi³

2007

Neuroimmunomodulation

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The strong inflammatory response observed in neurodegenerative diseases can depend on the impairment of the endogenous control of microglial activation, triggering the release of potentially detrimental factors such as cytokines, nitric oxide (NO) and superoxide anion (O₂^–·). Our aim was to study the activation of microglial cells and the transduction pathways involved in their modulation by IL-1β and TNF-α. Microglial and mixed glial cell cultures from neonatal rats were exposed to IFN-γ and/or IL-1β and TNF-α. We analyzed NO secretion and the activation of ERK and STAT1. We found that astrocytes modulated microglial cell activation, decreasing production of NO. IFN-γ induced an 18- to 25-fold increase in NO, associated to a 3- to 5-fold increase in ERK phosphorylation in microglial cultures. IL-1β, but not TNF-α, inhibited IFN-γ-induced production of NO in microglia by 87%. It also reduced IFN-γ-induced phosphoERK (pERK) by 40%, without affecting phosphoSTAT1 (pSTAT1). In contrast, in microglial cultures exposed to media conditioned by astrocytes, IL-1β did not inhibit pERK, whereas it reduced activation of STAT1. Inducible NO synthase expression induced by IFN-γ in microglial cultures was reduced when the activation of ERK was prevented. We propose that IL-1β modulates IFN-γ-induced production of oxidative molecules through cross talk between STAT1 and MAPK pathways, regulating the amplitude and duration of microglial activation. Modulation of ERK was observed at 30 min, whereas inhibition of pSTAT was observed later (at 4 h), indicating that it was an early and transient phenomenon.

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“…The presence of Aβ in the brain activates inflammatory cells, and tissue levels of pro-and anti-inflammatory mediators including cytokines and chemokines are altered. 53 In particular, the production and secretion of proinflammatory mediators may contribute to the initiation and progression of neurodegeneration by a variety of mechanisms. Proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, may play an important role in AD pathology and lead to increased production of nitric oxide through iNOS activation, neuronal stress, and further neuronal dysfunction and death.…”

Section: Discussionmentioning

confidence: 99%

Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models

Bernardi¹,

Frozza²,

Meneghetti³

et al. 2012

IJN

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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.

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Protection of rat primary hippocampal cultures from Aβ cytotoxicity by pro-inflammatory molecules is mediated by astrocytes

Cited by 57 publications

References 74 publications

Beneficial effects of melatonin in experimental models of Alzheimer disease1

Beneficial effects of melatonin in experimental models of Alzheimer disease1

Modulation by Astrocytes of Microglial Cell-Mediated Neuroinflammation: Effect on the Activation of Microglial Signaling Pathways

Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models

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Protection of rat primary hippocampal cultures from Aβ cytotoxicity by pro-inflammatory molecules is mediated by astrocytes

Cited by 57 publications

References 74 publications

Beneficial effects of melatonin in experimental models of Alzheimer disease1

Beneficial effects of melatonin in experimental models of Alzheimer disease1

Modulation by Astrocytes of Microglial Cell-Mediated Neuroinflammation: Effect on the Activation of Microglial Signaling Pathways

Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by A&beta;1-42 in Alzheimer&rsquo;s disease models

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Product

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Indomethacin-loaded lipid-core nanocapsules reduce the damage triggered by Aβ1-42 in Alzheimer’s disease models