Clavulanic acid protects neurons in pharmacological models of neurodegenerative diseases

Abstract

Clavulanic acid is a psychoactive compound with excellent blood-brain barrier permeability and safety profiles. Previous studies showed that clavulanic acid suppresses anxiety in rodents and in a primate model. In addition, clavulanic acid is thought to enhance sexual function in animal models via central nervous system (CNS) mechanisms. To further examine its potential as a CNSmodulating agent, we investigated the effects of clavulanic acid in neurotoxin-induced animal models that emulate neurodegenerative disease symptoms. Clavulanic acid was administered to rodents that were exposed to kainic acid or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Using histochemical staining of brain sections, we demonstrated that clavulanic acid protects hippocampal and dopaminergic neurons from toxin-induced acute death. We also observed that clavulanic acid improves motor function in MPTP-treated mice in a behavioral test. These data indicate that clavulanic acid may have neuroprotective effects and warrants further investigation of its therapeutic use in CNS disorders, such as Parkinson's and Alzheimer's disease. Drug Dev Res 71: 351-357, 2010.

Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking

“…Recently, it was demonstrated that clavulanic acid, at different effective dose ranges, possesses strong CNS modulating effects, including anti-anxiety effects in rodent and primate models [9], neuroprotective effects in Parkinson’s disease models in vivo [5] as well as enhanced sexual arousal in animal models through a proposed CNS-mediated mechanism [1]. These clavulanic acid-induced pharmacological activities may be due to the release of dopamine via clavulanic acid interaction with vesicle trafficking and fusion proteins Munc18-1 and Rab4.…”

“…Clavulanic acid decreases anxiety in rodent and primate models [9]. Further findings suggest that clavulanic acid is a neuroprotective agent in Parkinson’s models in vivo [5]. Clavulanic acid has also been shown to enhance sexual arousal in animal models, and this effect is hypothesized to be CNS-mediated [1].…”

Clavulanic acid inhibits MPP+-induced ROS generation and subsequent loss of dopaminergic cells

“…In these studies, clavulanic acid protected neurons in rodents exposed to kainic acid or MPTP. Furthermore, we observed that clavulanic acid improved motor function in MPTP-treated mice in a behavioral test (Huh et al, 2010). It is believed that PD is caused by the progressive degeneration and eventual death of dopaminergic neurons of the substantianigra (SN) (Samii et al, 2004).…”

“…Importantly, in neurotoxin-induced animal models, clavulanic acid has been shown to improve motor function (Huh et al, 2010) suggesting that it can be neuroprotective; however, the mechanism as how clavulanic acid can induce neuroprotection is not known. We demonstrate here that clavulanic acid abrogates the effects of the neurotoxin 1-methyl-4-phenylpyridinium (MPP + ) which mimics Parkinson’s disease (PD) by inducing neurodegeneration.…”

Comparative systems biology between human and animal models based on next-generation sequencing methods

“…However, if the pathophysiological processes are studied, especially for the complex diseases, then models should mimic clinical settings as closely as possible, otherwise the expected results may not be achieved or the findings of such studies will be of limited value. Accordingly, comparisons between human and animal models are becoming increasingly important for both clinical and fundamental applications (Alini et al, 2008;Cox et al, 2009;Fuentes et al, 2009;Huh et al, 2010;Merchenthaler & Shughrue, 2005;Nestler & Hyman, 2010;Northoff, 2009). Among the available strategies to assess this connection, comparative systems biology has begun attracting special attention (Cox et al, 2009).…”