TNF-α knockout and minocycline treatment attenuates blood–brain barrier leakage in MPTP-treated mice

Zhao, Chaohui; Ling, Zaodung; Newman, Mary B.; Bhatia, Ankush; Carvey, Paul M.

doi:10.1016/j.nbd.2006.11.012

Cited by 163 publications

(130 citation statements)

References 58 publications

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“…However, such differences were not observed 24 h after pMCAo, when microglial numbers were similar in TNF-KO and WT mice. In support of our findings, significantly fewer activated microglia have been observed in the striatum and substantia nigra of TNF-KO mice in a model for Parkinson's disease (Zhao et al, 2007).…”

Section: Discussionsupporting

confidence: 90%

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lambertsen¹,

Clausen²,

Babcock³

et al. 2009

J. Neurosci.

335

352

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Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infarction and behavioral deficit are significantly exacerbated in TNF-knock-out (KO) mice compared with wild-type mice. By using in situ hybridization, immunohistochemistry, and green fluorescent protein bone marrow (BM)-chimeric mice, TNF was shown to be produced by microglia and infiltrating leukocytes. Additional analysis demonstrating that BM-chimeric TNF-KO mice grafted with wild-type BM cells developed larger infarcts than BM-chimeric wild-type mice grafted with TNF-KO BM cells provided evidence that the neuroprotective effect of TNF was attributable to microglial-not leukocyte-derived TNF. In addition, observation of increased infarction in TNF-p55 receptor (TNF-p55R)-KO mice compared with TNF-p75R and wild-type mice suggested that microglialderived TNF exerts neuroprotective effects through TNF-p55R. We finally report that TNF deficiency is associated with reduced microglial population size and Toll-like receptor 2 expression in unmanipulated brain, which might also influence the neuronal response to injury. Our results identify microglia and microglial-derived TNF as playing a key role in determining the survival of endangered neurons in cerebral ischemia.

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Section: Discussionsupporting

confidence: 90%

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lambertsen¹,

Clausen²,

Babcock³

et al. 2009

J. Neurosci.

335

352

View full text Add to dashboard Cite

show abstract

“…18 This effect could be mediated by inhibition of TNF-a production, since a similar protective effect was observed in TNF-a knockout or in wildtype mice that were treated with minocycline prior to the intraparenchymal injection of a dopamine neurotoxin. 28 Minocycline may also have therapeutic benefit for the treatment of HIV-induced neuroinflammation, as minocycline reduced the severity of encephalitis, suppressed viral load in the brain and decreased the expression of brain inflammatory markers in a Simian immunodeficiency model of HIV. 29 Further, inhibition of spinal cord microglial activation and cytokine expression by intrathecal administration of minocycline attenuated lowthreshold mechanical allodynia in two rat models of pain facilitation.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,123

992

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Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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“…In addition to ROS, microglia-derived proinflammatory cytokines may be involved in nigrostriatal DA neuronal death. Several lines of evidence highlight the presence of activated glial cells expressing the proinflammatory cytokines IL-1b and TNF-a in the SN of PD patients (68) and MPTP-treated mice (69). IL-1b and TNF-a originating from activated glial cells may trigger intracellular death-related signaling pathways in the MPTP model of PD (70).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

111

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This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

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TNF-α knockout and minocycline treatment attenuates blood–brain barrier leakage in MPTP-treated mice

Cited by 163 publications

References 58 publications

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Microglia Protect Neurons against Ischemia by Synthesis of Tumor Necrosis Factor

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

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