Neuroprotective and Anti–Human Immunodeficiency Virus Activity of Minocycline

Zink, M. Christine; Uhrlaub, Jennifer L.; DeWitt, Jesse; Voelker, Tauni; Bullock, Brandon; Mankowski, Joseph L.; Tarwater, Patrick M.; Clements, Janice E.; Barber, Sheila A.

doi:10.1001/jama.293.16.2003

Cited by 204 publications

(182 citation statements)

References 42 publications

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“…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. 30 The anti-inflammatory effects of minocycline extend to the clinic.…”

Section: Discussionmentioning

confidence: 94%

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

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,081

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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Section: Discussionmentioning

confidence: 94%

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

O’Connor

Lawson²,

André³

et al. 2008

Mol Psychiatry

1,081

992

View full text Add to dashboard Cite

show abstract

“…These factors include, but are not limited to, the HIV-1 proteins such as gp120 and tat, proinflammatory cytokines, arachidonic acid and its metabolites, quinolinic acid, and glutamate (42)(43)(44). Prior works performed in animal models and in humans have shown that adjunctive microglial immune modulatory drugs can affect HIV-1-associated cognitive decline (43,(45)(46)(47). Such neuroprotective therapies interrupt direct damage to neurons by attenuating the effects of macrophage activation.…”

Section: Discussionmentioning

confidence: 99%

Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis

Gorantla

Liu²,

Sneller

et al. 2007

The Journal of Immunology

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Copolymer-1 (COP-1) elicits neuroprotective activities in a wide range of neurodegenerative disorders. This occurs, in part, by adaptive immune-mediated suppression of microglial inflammatory responses. Because HIV infection and immune activation of perivascular macrophages and microglia drive a metabolic encephalopathy, we reasoned that COP-1 could be developed as an adjunctive therapy for disease. To test this, we developed a novel animal model system that reflects HIV-1 encephalitis in rodents with both innate and adaptive arms of the immune system. Bone marrow-derived macrophages were infected with HIV-1/vesicular stomatitis-pseudotyped virus and stereotactically injected into the basal ganglia of syngeneic mice. HIV-1 pseudotyped with vesicular stomatitis virus envelope-infected bone marrow-derived macrophages induced significant neuroinflammation, including astrogliosis and microglial activation with subsequent neuronal damage. Importantly, COP-1 immunization reduced astro- and microgliosis while diminishing neurodegeneration. Hippocampal neurogenesis was, in part, restored. This paralleled reductions in proinflammatory cytokines, including TNF-α and IL-1β, and inducible NO synthase, and increases in brain-derived neurotrophic factor. Ingress of Foxp3- and IL-4-expressing lymphocytes into brains of COP-1-immunized animals was observed. We conclude that COP-1 may warrant therapeutic consideration for HIV-1-associated cognitive impairments.

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“…Minocycline is a tetracycline derivative capable of crossing the blood brain barrier (Aronson, 1980), and can suppress inflammation, viral replication, and apoptosis (Irani and Prow, 2007;Michaelis et al, 2007;Mishra and Basu, 2008;Richardson-Burns and Tyler, 2005;Zink et al, 2005). Minocycline (90 mg/kg) was dissolved in phosphate-buffered-saline (PBS; pH=7.4) and administered intraperitoneally (Fan et al, 2005), concurrently with the ICV injections of POLY I:C at P14 in an attempt to interfere with inflammation and attenuate any long-term changes induced by POLY I:C.…”

Section: Minocycline Injectionsmentioning

confidence: 99%

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

Galic

Riazi

Henderson

et al. 2009

Neurobiology of Disease

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Viral infections of the CNS and their accompanying inflammation can cause long-term neurological effects, including increased risk for seizures. To examine the effects of CNS inflammation, we infused polyinosinic: polycytidylic acid, intracerebroventricularly to mimic a viral CNS infection in 14 day-old rats. This caused fever and an increase in the pro-inflammatory cytokine, interleukin (IL)-1β in the brain. As young adults, these animals were more susceptible to lithium-pilocarpine and pentylenetetrazol-induced seizures and showed memory deficits in fear conditioning. Whereas there was no alteration in adult hippocampal cytokine levels, we found a marked increase in NMDA (NR2A and C) and AMPA (GluR1) glutamate receptor subunit mRNA expression. The increase in seizure susceptibility, glutamate receptor subunits, and hippocampal IL-1β levels were suppressed by neonatal systemic minocycline. Thus, a novel model of viral CNS inflammation reveals pathophysiological relationships between brain cytokines, glutamate receptors, behaviour and seizures, which can be attenuated by anti-inflammatory agents like minocycline.

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Neuroprotective and Anti–Human Immunodeficiency Virus Activity of Minocycline

Cited by 204 publications

References 42 publications

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

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

Copolymer-1 Induces Adaptive Immune Anti-inflammatory Glial and Neuroprotective Responses in a Murine Model of HIV-1 Encephalitis

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

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