Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis

Lecca, Daniele; Jung, Yoo Jin; Scerba, Michael T.; Hwang, Inho; Kim, Yu Kyung; Kim, Sun; Modrow, Sydney; Tweedie, David; Hsueh, Shih-Chang; Liu, Dong; Luo, Weiming; Glotfelty, Elliot J.; Li, Yazhou; Wang, Jiayi; Luo, Yu; Hoffer, Barry J.; Kim, Do Kyung; McDevitt, Ross A.; Greig, Nigel H.

doi:10.1002/alz.12610

Cited by 62 publications

(39 citation statements)

References 101 publications

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“…Notably, conventional IMiDs have been described as inducing anti-inflammatory actions in both wild-type and cereblon-humanized mice [ 128 , 130 ]. The present communication and our prior studies [ 73 , 132 ] further support this separation of pathways underlying neuroinflammation, with some pathways being mediated via cereblon and others being independent of it. In the current study, we show that the novel thalidomide-like compound F-3,6′-DP effectively ameliorates systemic and brain inflammation, but although it binds to the key protein cereblon, it does not efficiently trigger the degradation of transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses induced by this drug class, thereby providing a different profile to pomalidomide.…”

Section: Discussionsupporting

confidence: 87%

“…In this study, we assessed the efficacy of F-3,6′-DP, a novel fluorinated dithio-pomalidomide structural analog [ 71 ], in both in vitro and in vivo models. Fluorine has been widely utilized in novel drug synthesis to reduce metabolism [ 72 ], and thionation on the pomalidomide backbone could potentially disrupt cereblon-dependent ubiquitination on several neo-substrates, such as SALL4, Aiolos, and Ikaros [ 73 , 74 ], which contribute to the teratogenic and anticancer properties of this class of drug [ 75 , 76 ]. In the current study, we evaluated the cereblon binding of F-3,6′-DP and its actions on neo-substrates, as well as whether F-3,6′-DP can efficiently reduce inflammatory mediators in cellular and rodent models of lipopolysaccharide (LPS)-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury

et al. 2022

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Traumatic brain injury (TBI) is a major risk factor for several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Neuroinflammation is a cause of later secondary cell death following TBI, has the potential to aggravate the initial impact, and provides a therapeutic target, albeit that has failed to translate into clinical trial success. Thalidomide-like compounds have neuroinflammation reduction properties across cellular and animal models of TBI and neurodegenerative disorders. They lower the generation of proinflammatory cytokines, particularly TNF-α which is pivotal in microglial cell activation. Unfortunately, thalidomide-like drugs possess adverse effects in humans before achieving anti-inflammatory drug levels. We developed F-3,6′-dithiopomalidomide (F-3,6′-DP) as a novel thalidomide-like compound to ameliorate inflammation. F-3,6′-DP binds to cereblon but does not efficiently trigger the degradation of the transcription factors (SALL4, Ikaros, and Aiolos) associated with the teratogenic and anti-proliferative responses of thalidomide-like drugs. We utilized a phenotypic drug discovery approach that employed cellular and animal models in the selection and development of F-3,6’-DP. F-3,6′-DP significantly mitigated LPS-induced inflammatory markers in RAW 264.7 cells, and lowered proinflammatory cytokine/chemokine levels in the plasma and brain of rats challenged with systemic LPS. We subsequently examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) in mice, a model of moderate TBI known to induce inflammation. F-3,6′-DP decreased CCI-induced neuroinflammation, neuronal loss, and behavioral deficits when administered after TBI. F-3,6′-DP represents a novel class of thalidomide-like drugs that do not lower classical cereblon-associated transcription factors but retain anti-inflammatory actions and possess efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury

et al. 2022

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“…3,6′-DP and 1,6′-DP lack activity in essential gatekeeper genotoxicity and hERG assays critical to human translation, and, in the light of their clear efficacy signal in the current study, they thus warrant further evaluation and development in preclinical animal models as candidate drugs to mitigate inflammation associated with excessive pro-inflammatory cytokine generation. In the light of the current data and recent favorable results of 3,6′-DP activity in a preclinical model of Alzheimer’s disease [ 69 ], future studies are focused towards evaluating the acute and chronic tolerability/toxicity of 3,6′- and 1,6′-DP in both male and female large and small animal species as a segue to potential human studies.…”

Section: Discussionmentioning

confidence: 99%

3,6′- and 1,6′-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation

Tsai

Kim²,

Hsueh

et al. 2022

Pharmaceutics

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(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′-dithiopomalidomide (3,6′-DP) and 1,6′-dithiopomalidomide (1,6′-DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti-inflammatory actions were characterized. (3) Results: Post-MCAo administration of all drugs lowered pro-inflammatory TNF-α and IL1-β levels, and reduced stroke-induced postural asymmetry and infarct size. Whereas 3,6′- and 1,6′-DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6′-DP did not lower Ikaros, Aiolos or SALL4 levels—critical intermediates mediating the anticancer/teratogenic actions of pomalidomide and IMiDs. 3,6′-DP and 1,6′-DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays –critical FDA regulatory tests. Finally, 3,6′- and 1,6′-DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α-synuclein and mouse LPS-challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF-α plays a key role in stroke outcome, and 3,6′-DP and 1,6′-DP may prove valuable as stroke therapies and thus warrant further preclinical development.

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“…Besides its main role as a master regulator of inflammation, TNF-α is a key player in the regulation of neuronal excitability, synaptic strength and plasticity [ 26 , 87 , 88 ]. Of note, TNF-α is elevated in several neurological diseases associated with memory and learning deficits [ 89 ] and plays an important role in age-related cognitive decline [ 90 ] and in Alzheimer disease-induced cognitive impairment [ 91 , 92 ]. For instance, by binding to the neuronal TNF receptor TNFR1, TNF-α inhibits theta-burst-induced long-term potentiation (LTP) in CA1 synapses [ 93 , 94 , 95 ] and mediates amyloid-beta-induced inhibition of LTP in the DG [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex

Palmas

Etzi

Pisanu

et al. 2022

Cells

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Parkinson’s disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease’s motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

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Role of chronic neuroinflammation in neuroplasticity and cognitive function: A hypothesis

Cited by 62 publications

References 101 publications

Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury

Activity of a Novel Anti-Inflammatory Agent F-3,6′-dithiopomalidomide as a Treatment for Traumatic Brain Injury

3,6′- and 1,6′-Dithiopomalidomide Mitigate Ischemic Stroke in Rats and Blunt Inflammation

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex

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