A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

Yrjänheikki, Juha; Tikka, Tiina; Keinänen, Riitta; Goldsteins, Gundars; Chan, Pak H.; Koistinaho, Jari

doi:10.1073/pnas.96.23.13496

Cited by 958 publications

(811 citation statements)

References 32 publications

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“…In animals, minocycline is lethal at very high doses (LD 50 :3600 mg/kg; Blum et al, 2004;Smith et al, 2003). In humans, long-term treatment with minocycline up to 200 mg/day is generally safe and well tolerated as In recent years, minocycline has been reported to have neuroprotective effects in various experimental neurodegenerative disease models such as cerebral ischemia (Yrjanheikki et al, 1999), traumatic brain injury (Sanchez Mejia et al, 2001), ALS (Zhu et al, 2002), PD (Wu et al, 2002), and HD (Chen et al, 2000;Wang et al, 2003). At present, a few number of studies are focused on the therapeutical potential of minocycline in AD (Hunter et al, 2004a;Seabrook et al, 2006), where it suppressed microglial production of IL-1beta, IL-6, TNF, and NGF in in vitro as well as APP transgenic mice (Seabrook et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its antibiotic properties, minocycline has been reported to have neuroprotective effects in various experimental models of cerebral ischemia (Yrjanheikki et al, 1999), traumatic brain injury (Sanchez Mejia et al, 2001), amyotrophic lateral sclerosis (ALS) (Zhu et al, 2002), Parkinson's diseases (PD) (Wu et al, 2002), kainic acid treatment (Heo et al, 2006), Huntington's disease (HD) (Chen et al, 2000;Wang et al, 2003), and multiple sclerosis (Popovic et al, 2002). Additionally, minocycline was reported to attenuate white matter damage in a rat model of chronic cerebral hypoperfusion .…”

Section: Introductionmentioning

confidence: 99%

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Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

256

179

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Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNAdependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 a and caspase 12 activation induced by amyloid b peptide 1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 a were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid b peptide 1-42 -infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid b peptide 1-42 -infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 a is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

256

179

View full text Add to dashboard Cite

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“…A similar long therapeutic time window in brain ischemia has been reported for other pharmacological strategies aimed at reducing post-ischemic inflammation (Iadecola et al, 1995;Nagayama et al, 1998;Cash et al, 2001). In addition, several studies have found neuroprotective effects of different compounds when administered after ischemia (Jiang et al, 1998;Yrjanheikki et al, 1999;Haag et al, 2000;Phillips et al, 2000;Zhang et al, 2001;Snider et al, 2001;Lavie et al, 2001;Mary et al, 2001), suggesting that brain injury produced by cerebral ischemia develops over a period of hours to days after the primary event.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Candelario‐Jalil

Alvarez

González-Falcón

et al. 2002

European Journal of Pharmacology

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Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils.Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 minutes before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34 ± 9 % protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia.

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“…Minocycline was shown to suppress microglial activation and improve neuronal survival after brain ischemia. 228,229 Minocycline and other PARP-1 inhibitors are entering clinical trials for treatment of stroke and other conditions. 230 -232 …”

Section: Other Factors That Influence Proinflammatory Gene Transcriptionmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

Cited by 958 publications

References 32 publications

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Microglial Activation in Stroke: Therapeutic Targets

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