Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation

Tikka, Tiina; Usenius, Taina; Tenhunen, Mikko; Keinänen, Riitta; Koistinaho, Jari

doi:10.1046/j.1471-4159.2001.00543.x

Cited by 85 publications

(59 citation statements)

References 35 publications

(57 reference statements)

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“…We found also that minocycline treatment inhibits both microglial proliferation and activation in lesioned mice, supporting the strong antiinflammatory effect of this drug (Yrjänheikki et al, 1998;Tikka et al, 2001a;Ekdahl et al, 2003). Minocycline is a potent inhibitor of microglial activation in vitro and in vivo, which dramatically decreases the activation of microglial NADPH-oxidase and the microglial production of proinflammatory cytokines and inducible nitric oxide synthase (Tikka and Koistinaho, 2001;Tikka et al, 2001b;Wu et al, 2002;Hutchinson et al, 2008). Inhibition of microglial activation using minocycline probably results from the blockage of cyclooxygenase-2 induction and the activation of stress-activated p38 mitogen-activated protein kinase, two key enzymes involved in the production of proinflammatory prostanoids, proinflammatory cytokines, and cytotoxic molecules including reactive oxygen species and nitric oxide (Yrjänheikki et al, 1999;Tikka et al, 2001a).…”

Section: Tuning the Survival Of Adult-born Neurons During Ob Inflammasupporting

confidence: 72%

Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb

Lazarini

Gabellec²,

Torquet³

et al. 2012

J. Neurosci.

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Microglia, the innate immune cells of the brain, engulf and eliminate cellular debris during brain injury and disease. Recent observations have extended their roles to the healthy brain, but the functional impact of activated microglia on neural plasticity has so far been elusive. To explore this issue, we investigated the role of microglia in the function of the adult olfactory bulb network in which both sensory afferents and local microcircuits are continuously molded by the arrival of adult-born neurons. We show here that the adult olfactory bulb hosts a large population of resident microglial cells. Deafferentation of the olfactory bulb resulted in a transient activation of microglia and a concomitant reduction of adult olfactory bulb neurogenesis. One day after sensory deafferentation, microglial cells proliferate in the olfactory bulb, and their numbers peaked at day 3, and reversed at day 7 after lesion. Similar lesions performed on immunodeficient mice demonstrate that the both innate and adaptive lymphocyte responses are dispensable for the lesion-induced microglial proliferation and activation. In contrast, when mice were treated with an antiinflammatory drug to prevent microglial activation, olfactory deafferentation did not reduce adult neurogenesis, showing that activated microglial cells per se, and not the lack of sensory experience, relates to the survival of adult-born neurons. We conclude that the status of the resident microglia in the olfactory bulb is an important factor directly regulating the survival of immature adult-born neurons.

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Section: Tuning the Survival Of Adult-born Neurons During Ob Inflammasupporting

confidence: 72%

Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb

Lazarini

Gabellec²,

Torquet³

et al. 2012

J. Neurosci.

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“…33,50,53,54 Interestingly, it has been recently demonstrated that Dox has significant protective effects on neurons against apoptosis induction and global ischemia. 74,75 Therefore, the actual adverse effects of Tat on the development, behavior, and neuropathology of the GT-tg mice would likely be much greater.…”

Section: Discussionmentioning

confidence: 99%

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Kim

Liu

Ruan

et al. 2003

The American Journal of Pathology

227

308

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The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together dem-

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“…Inhibition of microglial activation using minocycline has also been demonstrated in vitro (Tikka et al, 2001b) and in other experimental models of acute and chronic brain insults (Yrjanheikki et Tikka and Koistinaho, 2001;Tikka et al, 2001a) and results, presumably, from the blockade of p38 mitogen-activated protein kinase . It is believed that activated microglia exerts cytotoxic effects in the brain through two very different and yet complementary processes .…”

Section: Discussionmentioning

confidence: 79%

Role of Nitric Oxide in MPTP-Induced Dopaminergic Neuron Degeneration

Przedborski¹

2002

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SUPPLEMENTARY NOTESreport contains color We investigated the role of nitric oxide (NO) in MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopaminergic (DA) neuron death in this mouse model of Parkinson's Disease (PD). Our previous work demonstrated that the superoxide radical is involved in the MPTP neurotoxic process in SNpc DA neurons. SNpc DA neurons in mice overexpressing superoxide dismutase (SODl) were protected against MPTP-induced degeneration. Since the superoxide radical does not act alone, based on the oxidative stress hypothesis, in Specific Aim I, we demonstrated that neuronal NOS (nNOS) and inducible NOS (iNOS) are both players in MPTP-induced neurotoxicity to SNpc DA neurons. In Specific Aim n, we show that while nNOS has a role in MPTP toxicity to SNpc DA neurons, iNOS is the principle culprit here due to its upregulation in activated microglia. Peroxynitrite-induced alterations in protein tyrosine residues were demonstrated in striatum and ventral mibrain of MPTP-treated mice by measurement of nitrotyrosine, orthotyrosine and o,o-dityrosine in Specific Aim m. Furthermore, Specific Aim IV showed that proteins important to normal fimction in SNpc DA neurons, tyrosine hydroxylase and a-synuclein, are nitrated following MPTP exposure. We conclude that the superoxide radical and NO act in concert to mitiate and propagate DA neuronal death in the SNpc of MPTP-treated mice and in PD patients. SUBJECT TERMSParkinson's disease, MPTP, neurotoxin, superoxide dismutase, free radicals, nitric oxide, transgenic mice, knockout mice Body 5 Key Research Accomplishments 6Reportable Outcomes 8 Conclusions 14References 18Appendices 22 Department of Defense Annual Report (2002) INTRODUCTIONParkinson's disease (PD) is a common neurodegenerative disorder that affects about 1,000,000 North Americans alone and that occurs in 50,000 newly diagnosed patients each year (1). This disease is characterized mainly by tremor, rigidity, akinesia and postural instability (2) all attributed to a dramatic loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and of DA nerve terminals in the caudateputamen (3,4). Symptoms of PD can be alleviated vwth the use of levodopa and other dopamine agonists, however, they do not stop the progression of the disease. Many hypotheses abound as to the etiology of PD, however, it is the oxidative stress theory that seems to take precedence over the others. In previous studies (5,6), we have shown that reactive oxygen species (ROS) and reactive nitrogen species are involved in the PD neurodegenerative process. To demonstrate the involvement of these compounds in the PD neurodegenerative process, we have used l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a by-product of the chemical synthesis of a meperidine analogue with potent heroin-like effects (7). MPTP is a specific DA neurotoxin that replicates almost all of the hallmarks of PD in non-human primates and in various other mammalian species including a severe irreversible loss of DA neurons in the SNp...

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Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation

Cited by 85 publications

References 35 publications

Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb

Early Activation of Microglia Triggers Long-Lasting Impairment of Adult Neurogenesis in the Olfactory Bulb

Neuropathologies in Transgenic Mice Expressing Human Immunodeficiency Virus Type 1 Tat Protein under the Regulation of the Astrocyte-Specific Glial Fibrillary Acidic Protein Promoter and Doxycycline

Role of Nitric Oxide in MPTP-Induced Dopaminergic Neuron Degeneration

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