Elsevier

Behavioural Brain Research

Volume 364, 17 May 2019, Pages 149-156
Behavioural Brain Research

A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects

https://doi.org/10.1016/j.bbr.2019.02.020Get rights and content

Highlights

Abstract

Several neurodegenerative disorders, namely Parkinson’s disease dementia, dementia with Lewy bodies, and Alzheimer’s disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and β-amyloid (Aβ). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aβ metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF.

Section snippets

Introduction to ceftriaxone (CEF)

CEF is a cephalosporin antibiotic approved for clinical use by the FDA in 1984 as a broad-spectrum antibiotic for infections such as pneumonia [1], bacterial meningitis [2], and gonorrhea [3]. Because CEF has long been used clinically, its safety has been demonstrated [4,5]. Recently, neuronal protective effects of CEF were observed in animal models of neurodegenerative disorders, where CEF prevents cognitive and motor deficits; inhibits dopaminergic (DAergic) degeneration in the striatum and

CEF prevents behavioral and neuronal deficits in the rat model of Parkinson’s disease dementia (PDD)

Several neurological disorders are associated with excessive glutamate levels and deficits of GLT-1 expression [9,10]. Functional interactions between the glutamatergic and dopaminergic (DAergic) systems in the brain regulate motor and cognitive functions. DAergic degeneration causes parkinsonism [11], and atrophy in the hippocampal CA1 area results in anterograde amnesia [12]. Similarly, cell loss in the hippocampal CA1 area has been observed to be accompanied by cognitive deficits in a rat

CEF may be useful to treat α-synuclein (α-syn)- and β-amyloid (Aβ)-related neuronal disorders

Dementia with Lewy bodies (DLB), PDD, and Alzheimer’s disease (AD) are different disorders, but they exhibit common pathophysiological changes, where α-synucleinopathies and Aβ cause neuroinflammation and neurodegeneration. Therefore, these changes have been the center of focus in understanding the etiology of these neurodegenerative disorders [25], since elimination of α-syn and Aβ may prevent these disorders.

DLB was initially identified as a dementia syndrome with Lewy body pathology.

Beneficial effects of CEF on movement disorders

Alexander’s disease is a genetic disease characterized by progressive motor deterioration with no cure. A case report indicated that administration of CEF reversed the progression of neurodegeneration in a patient with adult-onset Alexander's disease and substantially improved her quality of life. Before CEF therapy, in a 2-year period, gait ataxia and dysarthria worsened from mild to marked; palatal myoclonus spread from the soft palate to lower facial muscles; and the patient complained of

Beneficial effects of CEF on ischemia, pain, and seizure

Disruption of homeostasis of glutamatergic neurotransmission, causing excitotoxicity and cell death, plays a pathophysiological role in cerebral ischemia. Middle cerebral artery occlusion increased glutamate release and suppressed astrocytic GLT-1 expression in the frontal cortex and hippocampus. CEF (200 mg/kg/day, IP) pretreatment suppressed these changes in rats, where enhanced GLT-1 mRNA and protein levels were observed after 3 and 5 days of treatment, respectively [19]. CEF-pretreated rats

Mechanisms of CEF effects on neurological disorders

Although various neurodegenerative diseases have their main causes, many of the diseases have some common pathophysiological features, such as glutamatergic hyperactivity, excitotoxicity, oxidative stress, neuroinflammation, and accumulation of harmful proteins. CEF exerts several pharmacological effects that inhibits the above pathological features and thus can ameliorate many different neurodegenerative diseases and their symptoms. The above pathophysiological features are involved in

Periodic administration of CEF

Because CEF has antibacterial activity, using it to treat chronic diseases should not result in drug resistance induced by long-term use. Basic studies have demonstrated that continuous long-term administration of CEF is not necessary because periodic administration is sufficient to produce neuronal and behavioral protections.

Activation of the GLT-1 promotor was observed 48 h after CEF (100 μM) treatment in a cell culture [6]. CEF (200 mg/kg/day, IP)-enhanced GLT-1 mRNA and protein expressions

Conclusion

Several neurodegenerative diseases share common pathophysiological features, such as (1) interaction of α-syn and Aβ to form Lewy bodies and (2) glutamate-related neurotoxicity. Recent studies have demonstrated that CEF prevents α-syn polymerization and accumulation, inhibits Aβ production, accelerates its elimination, increases GLT-1 expression, removes glutamate, reduces excitotoxicity, and enhances neurogenesis. Electrophysiological, neurochemical, and in vivo MEMRI studies suggest that CEF

Conflicts of interest

The authors declare no conflicts of interest for the material in the manuscript.

Acknowledgements

This work was supported by grants from the Ministry of Science and Technology (MOST 106-2410-H-040-003-MY2; MOST 104-2923-H-040-001-MY3; MOST 104-2314-B-040 -007-MY2), Chung Shan Medical University Hospital (CSH-2017-C-007), Taipei City Government (10501-62-046).

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