Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways

Ben‐Azu, Benneth; Omogbiya, Itivere Adrian; Aderibigbe, Adegbuyi Oladele; Umukoro, Solomon; Ajayi, Abayomi Mayowa; Iwalewa, Ezekiel O.

doi:10.1016/j.brainresbull.2018.02.007

Cited by 43 publications

(12 citation statements)

References 72 publications

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“…Disturbances in the balance between the antioxidant enzymes CAT, SOD, and GSH-Px and H 2 O 2 and MDA lead to OS, and antioxidant therapy has been shown to be effective in improving symptoms of schizophrenia [41,42]. Evidence has shown that doxycycline, and antioxidant and anti-in ammatory agents, attenuated ketamine-induced schizophrenia-like behavior and enhanced the therapeutic effect of the antipsychotic risperidone in a mouse model of schizophrenia [43]. Several hypotheses have been proposed; for example, metabolism of the neurotransmitters dopamine and glutamate generates high levels of ROS that affect synaptic plasticity and signaling through NMDA and D2 receptors, and that imbalance in oxidative and antioxidant systems lead to DNA methylation and drive parvalbumin interneuron damage, which is associated with the symptoms of schizophrenia [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Variations of plasma oxidative stress levels in male patients with chronic schizophrenia: Correlations with psychopathology and matrix metalloproteinase-9

Yang,

Zhang,

Yang

et al. 2023

Preprint

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Background: Accumulating evidence has indicated that oxidative stress (OS) and matrix metalloproteinase-9 (MMP-9) may contribute to the mechanism of schizophrenia. In the present study, we aimed to evaluate the associations of OS parameters and MMP-9 levels with psychopathological symptoms in male chronic schizophrenia patients. Methods: Plasma hydrogen peroxide (H2O2), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), serum matrix metalloproteinase-9 (MMP-9), and tissue inhibitors of metalloproteinases-1 (TIMP-1) levels were assayed in 80 male patients with chronic schizophrenia and 80 matched healthy controls. Schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS). Results: Our results demonstrated that levels of antioxidant enzymes, SOD, GSH-Px, H2O2, and MDA were significantly decreased, whereas CAT and MMP-9 levels were increased in patients with schizophrenia, when compared with healthy controls (all P < 0.05). In schizophrenia patients, correlation analyses showed that H2O2 levels were significantly and positively correlated with PANSS positive scores, CAT and MDA levels were significant negatively correlated with PANSS negative scores and PANSS total scores, and MDA levels were significantly positively correlated with MMP-9 levels (all P < 0.05). However, we did not find that MMP-9 played an interaction role between OS parameters and PANSS total scores and subscales scores (all P > 0.05). Conclusions: Our results showed that alterations of plasma OS parameters in male patients with chronic schizophrenia were associated with psychopathology and MMP-9, suggesting that OS and neuroinflammation may play important role in the mechanism of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Variations of plasma oxidative stress levels in male patients with chronic schizophrenia: Correlations with psychopathology and matrix metalloproteinase-9

Yang,

Zhang,

Yang

et al. 2023

Preprint

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“…Neuroprotective effects of this drug have been described in prion disease, Alzheimer disease and multiple sclerosis patients (Griffin et al, 2010; Santa‐Cecília et al, 2019). Doxycycline can also modify neurotransmitter systems known to be involved in the pathophysiology of l ‐DOPA‐induced dyskinesia such as cholinergic and nitrergic systems (Ben‐Azu et al, 2018; Griffin et al, 2010). In addition to its anti‐inflammatory effect, doxycycline reshapes α‐synuclein oligomers and inhibits α‐synuclein aggregation and the seeding of new oligomers (González‐Lizárraga et al, 2017; Ruzza et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Doxycycline and its derivative, COL‐3, decrease dyskinesia induced by l‐DOPA in hemiparkinsonian rats

Bortolanza

Nascimento

Raisman‐Vozari

et al. 2021

British J Pharmacology

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Background and Purpose l‐DOPA‐induced dyskinesia is a debilitating effect of treating Parkinson's disease with this drug. New therapeutic approaches that prevent or attenuate this side effect are needed. Experimental Approach Wistar adult male rats submitted to 6‐hydroxydopamine‐induced unilateral medial forebrain bundle lesion were treated with l‐DOPA (p.o. 20 mg·kg−1 or s.c. 10 mg·kg−1) once a day for 14 days. After this period, we tested if doxycycline (40 mg·kg−1, i.p.) and COL‐3 (50 and 100 nmol, i.c.v.) could reverse l‐DOPA‐induced dyskinesia. In an additional experiment, doxycycline was administered together with l‐DOPA to verify if it would prevent l‐DOPA‐induced dyskinesia development. Key Results A single injection of doxycycline or COL‐3 attenuated l‐DOPA‐induced dyskinesia. Co‐treatment with doxycycline from the first day of l‐DOPA suppressed the onset of dyskinesia. The improved motor response after l‐DOPA was not affected by doxycycline or COL‐3. Doxycycline treatment was associated with decreased immunoreactivity of FosB, COX‐2, the astroglial protein GFAP and the microglial protein OX‐42, which were elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline decreased metalloproteinase‐2/‐9 activity, metalloproteinase‐3 expression and ROS production. Metalloproteinase‐2/‐9 activity and production of ROS in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia. Conclusion and Implications The present study demonstrates the anti‐dyskinetic potential of doxycycline and its analogue compound COL‐3 in hemiparkinsonian rats. Given the long‐established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or prevent l‐DOPA‐induced dyskinesia in Parkinson's patients.

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“…Ketamine-induced models treated with doxycycline had higher levels of reduced glutathione, catalase, and superoxide dismutase. Furthermore, treatment with doxycycline-enhanced risperidone (an inhibitor of dopaminergic and serotonergic pathway activity in the brain) effects by lowering locomotion activity, which suggests interference with dopaminergic transmission in mice models [ 316 ].…”

Section: Neuropsychiatric Diseases: Schizophrenia and Depressionmentioning

confidence: 99%

Neurodegeneration, Mitochondria, and Antibiotics

et al. 2023

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Neurodegenerative diseases are characterized by the progressive loss of neurons, synapses, dendrites, and myelin in the central and/or peripheral nervous system. Actual therapeutic options for patients are scarce and merely palliative. Although they affect millions of patients worldwide, the molecular mechanisms underlying these conditions remain unclear. Mitochondrial dysfunction is generally found in neurodegenerative diseases and is believed to be involved in the pathomechanisms of these disorders. Therefore, therapies aiming to improve mitochondrial function are promising approaches for neurodegeneration. Although mitochondrial-targeted treatments are limited, new research findings have unraveled the therapeutic potential of several groups of antibiotics. These drugs possess pleiotropic effects beyond their anti-microbial activity, such as anti-inflammatory or mitochondrial enhancer function. In this review, we will discuss the controversial use of antibiotics as potential therapies in neurodegenerative diseases.

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Doxycycline prevents and reverses schizophrenic-like behaviors induced by ketamine in mice via modulation of oxidative, nitrergic and cholinergic pathways

Cited by 43 publications

References 72 publications

Variations of plasma oxidative stress levels in male patients with chronic schizophrenia: Correlations with psychopathology and matrix metalloproteinase-9

Variations of plasma oxidative stress levels in male patients with chronic schizophrenia: Correlations with psychopathology and matrix metalloproteinase-9

Doxycycline and its derivative, COL‐3, decrease dyskinesia induced by l‐DOPA in hemiparkinsonian rats

Neurodegeneration, Mitochondria, and Antibiotics

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