Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation

Peña-Altamira, Emiliano; Prati, Federica; Massenzio, Francesca; Virgili, Marco; Contestabile, Antonio; Bolognesi, María Laura; Monti, Barbara

doi:10.1517/14728222.2016.1121237

Cited by 59 publications

(39 citation statements)

References 124 publications

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“…One study even suggests that anti-inflammatory drug treatment may be detrimental if given at the later stage of the disease (Keller et al, 2011). This therapeutic approach aiming to counteract general neuroinflammation has failed in several disease therapies as reviewed elsewhere (Pena-Altamira et al, 2016). Collectively, these studies indicate that the non-specific inflammatory blockade is unlikely to be beneficial for the disease treatment.…”

Section: Regulators Of Microglial Activation Statesmentioning

confidence: 99%

“…Other novel potential microglial targets for immunomodulation are reviewed elsewhere (Pena-Altamira et al, 2016). These approaches include the following targets: (1) 5′ adenosine monophosphate-activated protein kinase (AMPK): a critical enzyme in cellular energy homeostasis, (2) microglia-produced high-mobility group box-1 (HMGB1): an early released pro-inflammatory cytokine, (3) glycogen synthase kinase-3β (GSK3β): an enzyme that mediates microglial migration and inflammation-induced neurotoxicity, and (4) histone deacetylases (HDACs).…”

Section: Novel Microglial Targetsmentioning

confidence: 99%

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Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Subramaniam

Federoff

2017

Front. Aging Neurosci.

263

240

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Parkinson’s disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis. Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD and a better understanding is essential for developing putative neuroprotective agents. Targeting microglial activation states by suppressing their deleterious pro-inflammatory neurotoxicity and/or simultaneously enhancing their beneficial anti-inflammatory protective functions appear as a valid therapeutic approach for PD treatment. In this review, we summarize microglial functions and, their dual neurotoxic and neuroprotective role in PD. We also review molecules that modulate microglial activation states as a therapeutic option for PD treatment.

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Section: Regulators Of Microglial Activation Statesmentioning

confidence: 99%

Section: Novel Microglial Targetsmentioning

confidence: 99%

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Subramaniam

Federoff

2017

Front. Aging Neurosci.

263

240

View full text Add to dashboard Cite

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“…In fact, 5 was able to shift microglia phenotype from M1 to M2, with no changes in microglial phagocytic activity. This lends support to the innovative concept of targeting microglial cells by modulating their activity, rather than simply trying to counteract their inflammatory neurotoxicity [55]. The advantage of immunomodulation is that it reduces neuroinflammation and toxicity, while at the same time strengthening intrinsic neuroprotective properties of microglia and promoting neuroregeneration.…”

Section: Fbdd Applied To the Discovery Of Anti-ad Lead Candidatesmentioning

confidence: 78%

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

2016

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Abstract:Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer's disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid-and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.

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“…The search for compounds that can effectively reduce neuroinflammation is a new strategy for improving the pharmacotherapy of neurodegenerative diseases28, 29, 30. PHPB has been shown to provide effective neuroprotection in previous studies by our group19, 20, 21, 22.…”

Section: Discussionmentioning

confidence: 99%

Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice

Zhao

Hou

Lei

et al. 2017

Acta Pharmaceutica Sinica B

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A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer׳s disease (AD). In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Levels of iNOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1 (HO-1) in the cortex and hippocampus. PHPB reduced the levels of iNOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.

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Changing paradigm to target microglia in neurodegenerative diseases: from anti-inflammatory strategy to active immunomodulation

Cited by 59 publications

References 124 publications

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

Potassium 2-(l-hydroxypentyl)-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice

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