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 40 publications

(5 citation statements)

References 72 publications

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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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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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“…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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“…Clinical and preclinical studies have reported that ketamine injections, both acute and subchronic, lead to memory impairments in humans [ 69 ], monkeys [ 70 ], and rodents [ 71 , 72 , 73 ]. Ketamine has also been shown to impair spontaneous alterations as a function of spatial working memory [ 74 , 75 ]. Moreover, ketamine can exert anxiety-like behavior [ 76 , 77 ], altered social behavior [ 78 , 79 ], hyperlocomotion [ 66 , 80 ], and impaired sensorimotor gating [ 81 , 82 ].…”

Section: Pharmacological Modelsmentioning

confidence: 99%

Advantages and Limitations of Animal Schizophrenia Models

Białoń

Wąsik

2022

IJMS

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Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.

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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 40 publications

References 72 publications

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

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

Neurodegeneration, Mitochondria, and Antibiotics

Advantages and Limitations of Animal Schizophrenia Models

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