Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABAAR and hypothermic effects

Sarnowska, Anna; Beresewicz, M; Zabłocka, Barbara; Domańska-Janik, Krystyna

doi:10.1016/j.neuint.2009.01.024

Cited by 54 publications

(38 citation statements)

References 52 publications

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“…Wilms et al (36) have shown that midazolam, clonazepam, and diazepam interfered with the in vitro synthesis and release of proinflammatory cytokines by microglia cells. In vivo, it has been shown that diazepam protected against neuronal death in the hippocampus after transient forebrain ischemia (37). Benzodiazepines, like antipsychotics, decreased neuroinflammation rather than were responsible for the increased 11 C-(R)-PK11195 binding potential in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

Doorduin¹,

Vries²,

Willemsen³

et al. 2009

J Nucl Med

513

348

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Section: Discussionmentioning

confidence: 99%

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

Doorduin¹,

Vries²,

Willemsen³

et al. 2009

J Nucl Med

513

348

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“…Above them, PK11195 has been investigated in vitro, using a model of human microglia injured with lipopolysaccharide (LPS) or platelet-activating factor (PAF); data have evidenced [49,50] that, at micromolar concentrations, PK11195 has inhibited the LPS-induced up-regulation of inflammatory factors [cyclooxygenase-2 (COX-2) and tumour necrosis factor-α (TNF-α)], probably modulating the Ca 2 + -mediated signalling pathways [40,41]. PK11195 has been also studied, at nanomolar concentrations in rat microglia, evidencing an increase in proliferation, phagocytosis and reactive oxygen species (ROS) production [42].…”

Section: Tspo Ligands In the Treatment Of Neuro-inflammationmentioning

confidence: 99%

Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection

Pozzo

Giacomelli

Barresi

et al. 2015

Biochemical Society Transactions

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The translocator protein (TSPO, 18 kDa), mainly localized in the outer mitochondrial membrane of steroidogenic tissues, is involved in several cellular functions. TSPO level alterations have been reported in a number of human disorders, particularly in cancer, psychiatric and neurological diseases. In the central nervous system (CNS), TSPO is usually expressed in glial cells, but also in some neuronal cell types. Interestingly, the expression of TSPO on glial cells rises after brain injury and increased TSPO expression is often observed in neurological disorders, gliomas, encephalitis and traumatic injury. Since TSPO is up-regulated in brain diseases, several structurally different classes of ligands targeting TSPO have been described as potential diagnostic or therapeutic agents. Recent researches have reported that TSPO ligands might be valuable in the treatment of brain diseases. This review focuses on currently available TSPO ligands, as useful tools for the treatment of neurodegeneration, neuro-inflammation and neurotrauma.

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“…In humans or experimental animals, mitochondrial defects are often observed in a variety of CNS disorders and brain aging [66]. BZD has been reported for both beneficial [67] and adverse [68,69] effects on mitochondria. BZD (diazepam) blocked the apoptotic release of cytochrome c from mitochondria [67], suggesting that BZD has a mito-protective effect.…”

Section: Discussionmentioning

confidence: 99%

“…BZD has been reported for both beneficial [67] and adverse [68,69] effects on mitochondria. BZD (diazepam) blocked the apoptotic release of cytochrome c from mitochondria [67], suggesting that BZD has a mito-protective effect. In contrast, several BZDs including diazepam, suppressed mitochondrial respiratory control ratio (State III/State IV) in rat kidney [70].…”

Section: Discussionmentioning

confidence: 99%

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

Jung¹,

Metzger²

2013

ABB

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Benzodiazepine (BZD) is the most prescribed CNS depressant in America to treat hyper-excitatory disorders such as anxiety and insomnia. However, the chronic use of BZD often creates adverse effects including psychomotor deficit. In this study, we investigated a novel mechanism by which chronic BZD impedes motoric function in female mice. We used female mice because BZD use is much more prevalent in female than male populations. We tested the hypothesis that the accumulation of p38 (stress-activated protein) in cerebellar Purkinje neurons mediates motoric deficit induced by chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 in cerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38 loxP/loxP mice. p38-knockdown mice and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During this period, they were tested for motoric performance using Rotarod assay in which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum was then collected to detect p38 in Purkinje neurons and to measure mitochondrial respiration using immunohistochemistry and real-time XF respirometry, respectively. Compared to vehicletreated mice, BZD-treated mice showed poorer motoric performance, a higher number of Purkinje neurons containing p38, and lower mitochondrial respiration. These effects of BZD were much smaller in p38-knockdown mice. These results suggest that the excessive accumulation of p38 in cerebellar Purkinje neurons contributes to motoric deficit associated with chronic BZD. They also suggest that Purkinje neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in cerebellum. Our findings may provide a new mechanistic insight into chronic BZD-induced motoric deficit.

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Diazepam neuroprotection in excitotoxic and oxidative stress involves a mitochondrial mechanism additional to the GABAAR and hypothermic effects

Cited by 54 publications

References 52 publications

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

Neuroinflammation in Schizophrenia-Related Psychosis: A PET Study

Targeting the 18-kDa translocator protein: recent perspectives for neuroprotection

Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

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