Calcitonin gene-related peptide decreases IL-1beta, IL-6 as well as Ym1, Arg1, CD163 expression in a brain tissue context-dependent manner while ameliorating experimental autoimmune encephalomyelitis

Rossetti, Ilaria; Zambusi, Laura; Finardi, Annamaria; Bodini, Alessandro; Provini, L.; Furlan, Roberto; Morara, Stefano

doi:10.1016/j.jneuroim.2018.07.005

Cited by 17 publications

(18 citation statements)

References 48 publications

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“…This might be relevant clinically for people with MS, a condition in which the prevalence of migraines is three times greater than in the general population, and in which the BBB is compromised for up to several months after a flare‐up . As we have seen, CGRP, injected into a cerebral ventricle, reduces disease severity in an animal model of MS …”

Section: Neuroprotective Consequences Of Cgrp Outside the Blood‐brainmentioning

confidence: 77%

“…In addition to neurons, other types of brain cells including astrocytes, oligodendrocytes, and microglia have receptors for CGRP . In particular, microglia appear to be partially deactivated by CGRP injected directly into cerebrospinal fluid, leading to reduced neuroinflammation and disease severity in an animal model of multiple sclerosis (MS) . This effect is stimulus‐ and tissue‐specific.…”

Section: Neuroprotective Properties Of Cgrp Within the Brainmentioning

confidence: 99%

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CGRP and Brain Functioning: Cautions for Migraine Treatment

Borkum

2019

Headache

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Background Calcitonin gene‐related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long‐term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning. Methods Qualitative review of the preclinical literature on CGRP in brain physiology and pathophysiology. Results Within the brain, CGRP is upregulated by stresses such as ischemia, injury, hyperthermia, and seizure, and activates neuroprotective processes. Thus, CGRP buffers intracellular calcium, triggers antiapoptotic signaling, upregulates a number of neurotrophins (including insulin‐like growth factor‐1/IGF‐1, basic fibroblast growth factor/bFGF, and nerve growth factor/NGF), reduces brain edema, and likely increases antioxidant defenses. When released outside the blood‐brain barrier, CGRP likely protects the endothelium, upregulates growth factor signaling from the endothelium to the brain parenchyma, strengthens the blood‐brain barrier, protects the immune privilege of the brain by inhibiting the movement of neutrophils and monocytes, and facilitates neurogenesis and angiogenesis at stem cell niches. Conclusions CGRP participates in a wide range of neuroprotective processes. In theory, migraineurs with comorbid brain pathology might be at increased risk from CGRP inhibition. However, the extent of compensating processes is unknown and will determine whether these risks materialize in practice.

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Section: Neuroprotective Consequences Of Cgrp Outside the Blood‐brainmentioning

confidence: 77%

Section: Neuroprotective Properties Of Cgrp Within the Brainmentioning

confidence: 99%

CGRP and Brain Functioning: Cautions for Migraine Treatment

Borkum

2019

Headache

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“…The pro-inflammatory phenotype of microglia is closely linked with an increased expression of P2X purinoceptor 4 (P2X4R), P2X7R, P2Y12R, Inducible Nitric Oxide Synthase (iNOS), Cyclooxygenase 2 (COX-2), and CD68. Oppositely, the alternative or anti-inflammatory phenotype of microglia is associated with a high expression of CD163 and arginase 1 [16,17,22,[31][32][33]. In neuron/glia cultures, LPS/IFN-γ elevated the protein levels of P2X4R, P2X7R, P2Y12R, iNOS, COX-2 ( Figure 3A), and CD68 ( Figure 2C) while had little effect on the mRNA levels of CD163 and arginase 1 ( Figure 3B).…”

Section: β-Funaltrexamine Alleviated Microglia Activationmentioning

confidence: 99%

“…Neuron/glia consisted of 30-40% neurons, 40-50% astrocytes, and 10-15% microglia. The murine microglia BV2 cell line and macrophage RAW264.7 cell line were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS [33].…”

Section: Cell Culturesmentioning

confidence: 99%

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

Chang

Shih

et al. 2020

IJMS

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Chronic treatment involving opioids exacerbates both the risk and severity of ischemic stroke. We have provided experimental evidence showing the anti-inflammatory and neuroprotective effects of the μ opioid receptor antagonist β-funaltrexamine for neurodegenerative diseases in rat neuron/glia cultures and a rat model of cerebral Ischemia/Reperfusion (I/R) injury. Independent of in vitro Lipopolysaccharide (LPS)/interferon (IFN-γ)-stimulated neuron/glia cultures and in vivo cerebral I/R injury in Sprague–Dawley rats, β-funaltrexamine downregulated neuroinflammation and ameliorated neuronal degeneration. Alterations in microglia polarization favoring the classical activation state occurred in LPS/IFN-γ-stimulated neuron/glia cultures and cerebral I/R-injured cortical brains. β-funaltrexamine shifted the polarization of microglia towards the anti-inflammatory phenotype, as evidenced by decreased nitric oxide, tumor necrosis factor-α, interleukin-1β, and prostaglandin E2, along with increased CD163 and arginase 1. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by β-funaltrexamine was accompanied by the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein, along with signal transducers and activators of transcription transcriptional activities and associated upstream activators. The effects of β-funaltrexamine are closely linked with its action on neuroinflammation by switching microglia polarization from pro-inflammatory towards anti-inflammatory phenotypes. These findings provide new insights into the anti-inflammatory and neuroprotective mechanisms of β-funaltrexamine in combating neurodegenerative diseases, such as stroke.

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“…Moreover, in a rat model of inflammatory bowel disease and experimental colitis, neutralization of CGRP accentuated disease (Reinshagen et al, 1998;Reinshagen et al, 2000). In experimental autoimmune encephalomyelitis, CGRP reduces inflammation (Rossetti et al, 2018). Taken together, these studies indicate that CGRP plays a role as an anti-inflammatory mediator responsible for preventing tissue damage during inflammation or injury.…”

Section: Calcitonin Gene-related Peptide (Cgrp)mentioning

confidence: 99%

Interaction of neurotransmitters and neurochemicals with lymphocytes

Kerage

Sloan

Mattarollo

et al. 2019

Journal of Neuroimmunology

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Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed. As defined above, a neurotransmitter must be produced by neurons. Lymphocytes can be exposed to neurotransmitters in the blood or tissue. T-cells entering the central nervous system (CNS) encounter neurotransmitters at the site of release from neurons. Neurotransmitters are also found in blood. For example, acetylcholine can be detected in

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Calcitonin gene-related peptide decreases IL-1beta, IL-6 as well as Ym1, Arg1, CD163 expression in a brain tissue context-dependent manner while ameliorating experimental autoimmune encephalomyelitis

Cited by 17 publications

References 48 publications

CGRP and Brain Functioning: Cautions for Migraine Treatment

CGRP and Brain Functioning: Cautions for Migraine Treatment

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

Interaction of neurotransmitters and neurochemicals with lymphocytes

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