Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Pennisi, Manuela; Crupi, Rosalia; Paola, Rosanna Di; Ontario, Maria Laura; Bella, Rita; Calabrese, Edward J.; Crea, Roberto; Cuzzocrea, Salvatore; Calabrese, Vittorio

doi:10.1002/jnr.23986

Cited by 131 publications

(75 citation statements)

References 148 publications

(172 reference statements)

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“…Of all inflammasomes, the NLRP3 inflammasome is the most important member. NLRP3 inflammasome is a component of the innate immune system which can promote the maturation of pro-inflammatory cytokines IL-1β and IL-18, thus initiating inflammatory responses (21). In fact, several studies found that the assembly of NLRP3 inflammasome, the activation of caspase-1 and the release of IL-1β and IL-18 during TBI, indicating NLRP3 was involved in TBI pathology (8,22,23).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1

Zou

Liu

Li³

et al. 2017

Mol Med Report

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The inflammatory response in the cerebral cortex serves an important role in the progression of secondary injury following traumatic brain injury (TBI). The NLR family pyrin domain containing 3 (NLRP3) inflammasome is necessary for initiating inflammation and is involved in various central nervous system disorders. The aim of the present study was to investigate the neuroprotective effect of resveratrol and elucidate the underlying mechanisms of resveratrol associated regulation of the NLRP3 inflammasome in TBI. The results demonstrated that the activation of NLRP3, caspase‑1 and sirtuin 1 (SIRT1), enhanced the production of inflammatory cytokines and reactive oxygen species (ROS) following TBI. Administration of resveratrol alleviated the degree of TBI, as evidenced by the reduced neuron‑specific enolase (NSE) and brain water content (WBC). Resveratrol pretreatment also inhibited the activation of NLRP3 and caspase‑1, and reduced the production of inflammatory cytokines and ROS. In addition, resveratrol further promoted SIRT1 activation. Furthermore, the suppressing effect of resveratrol on the NLRP3 inflammasome and ROS was blocked by the SIRT1 inhibitor, sirtinol. The results revealed that the activation of the NLRP3 inflammasome and the subsequent inflammatory responses in the cerebral cortex were involved in the process of TBI. Resveratrol may attenuate the inflammatory response and relieve TBI by reducing ROS production and inhibiting NLRP3 activation. The effect of resveratrol on NLRP3 inflammasome and ROS may also be SIRT1 dependent.

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Section: Discussionmentioning

confidence: 99%

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1

Zou

Liu

Li³

et al. 2017

Mol Med Report

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“…Additionally, astrocytes, neurons, brain pericytes, T cells and mast cells also play a significant role in the brain inflammatory mechanisms. Inflammatory mediators, neurotoxic mediators, inflammasomes and hormones released by the activated glial cells and injured neurons are involved in neuroinflammation in AD and PD pathogenesis (Tufekci et al, 2012; Pennisi et al, 2016; Becher et al, 2017; Gualtierotti et al, 2017; Rustenhoven et al, 2017; Sawikr et al, 2017; Song et al, 2017). Substantia nigra has the highest density of microglial cells, which are found, to be activated in PD brains.…”

Section: Introductionmentioning

confidence: 99%

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

Kempuraj

Thangavel

Selvakumar

et al. 2017

Front. Cell. Neurosci.

359

265

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Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson’s disease (PD), Alzheimer’s disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1–42 (Aβ1–42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can also enter into the peripheral system through defective BBB, recruit immune cells into the brain, and exacerbate neuroinflammation. We suggest that mast cell-associated inflammatory mediators from systemic inflammation and brain could augment neuroinflammation and neurodegeneration in the brain. This review article addresses the role of some atypical inflammatory mediators that are associated with mast cell inflammation and their activation of glial cells to induce neurodegeneration.

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“…Alzheimer's disease (AD) is a multifaceted, progressive neurodegenerative disease that includes several detrimental processes in the brain: neuroinflammation (Calsolaro & Edison, 2016;Pennisi et al, 2017); neurotransmitter system dysregulation (Correia, Perry, & Moreira, 2016); increased oxidative stress (Calabrese et al, 2018;Pennisi et al, 2017) and glucose and energy metabolism dysfunction (Abolhassani et al, 2017;Duran-Aniotz & Hetz, 2016). All of these impairments result in the accumulation of amyloid-beta (Aβ) and other misfolded proteins (Lithfous, Dufour, & Després, 2013).…”

Section: Introductionmentioning

confidence: 99%

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

Piļipenko

Narbute

Amara

et al. 2019

J of Neuroscience Research

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Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer’s disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma‐aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: “free” moiety attached to the position 4 of the 1,4‐dihydropyridine (DHP) ring, and two “crypto” moieties as part of the DHP scaffold. The “free” and “crypto” GABA moieties are linked by a peptide bond (–CONH–), resulting in a peptide‐mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di‐2‐ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA‐A and GABA‐B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide‐like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti‐dementia drugs.

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Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Cited by 131 publications

References 148 publications

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

GABA‐containing compound gammapyrone protects against brain impairments in Alzheimer’s disease model male rats and prevents mitochondrial dysfunction in cell culture

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