Ceftriaxone Ameliorates Motor Deficits and Protects Dopaminergic Neurons in 6-Hydroxydopamine-Lesioned Rats

Abstract

Parkinson's disease is caused by the degeneration of dopaminergic neurons in substantia nigra. There is no current promising treatment for neuroprotection of dopaminergic neurons. Ceftriaxone is a beta-lactam antibiotic and has been reported to offer neuroprotective effects (Rothstein, J.-D., Patel, S., Regan, M.-R., Haenggeli, C., Huang, Y.-H., Bergles, D.-E., Jin, L., Dykes, H.-M., Vidensky, S., Chung, D.-S., Toan, S.-V., Bruijn, L.-I., Su, Z.-Z., Gupta, P., and Fisher, P.-B. (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression Nature433, 73-77). In the present study, efficacy of ceftriaxone in neuroprotection of dopaminergic neurons and amelioration of motor deficits in a rat model of Parkinson's disease were investigated. Ceftriaxone was administrated in 6-hydroxydopamine-lesioned rats. Using behavioral tests, grip strength and numbers of apomorphine-induced contralateral rotation were declined in the ceftriaxone-treated group. More importantly, cell death of dopaminergic neurons was found to decrease. In addition, both the protein expression and immunoreactivity for GLT-1 were up-regulated. The present results strongly indicate that ceftriaxone is a potential agent in the treatment of Parkinson's disease.

Ceftriaxone Blocks the Polymerization of α-Synuclein and Exerts Neuroprotective Effects in Vitro

“…During the preparation of this paper, Leung and co-workers 6 reported the efficacy of ceftriaxone in neuroprotection of Amino acid residues (circles) are shown as follows: hydrophobic residues (green interior), polar residues (light purple), basic residues (blue ring), and acidic residues (red ring). Differences in solvent accessible surface area for ceftriaxone and for protein residues are plotted as a blue smudge and a violet halo, respectively.…”

“…Additionally, the capability of ceftriaxone to reduce inflammation and apoptosis has been recently demonstrated. 30 Considering the Leung groups's experimental findings in an animal model of PD 6 and our data on the molecular interaction between ceftriaxone and α-synuclein, we thought to study the in vitro effects of ceftriaxone on viability and α-synuclein expression of PC12 cells exposed to 6-OHDA. Indeed, it is known that the treatment of neural cells with 6-OHDA reduces cell viability, 31 induces apoptosis, 32−34 and increases α-synuclein immunoreactivity.…”

“…5 In 2012, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons and amelioration of motor deficits in a rat model of Parkinson's disease (PD) was also documented. 6 However, which characteristics of ceftriaxone mediate its therapeutic effects in neurological disorders characterized by cellular accumulation of misfolded proteins, such as AxD and PD, it remains unclear. In particular, PD the second most common neurodegenerative disorder after Alzheimer's disease (AD), is essentially characterized by both the intraneuronal accumulation of misfolded fibrillar α-synuclein, in Lewy bodies and Lewy neuritis, and the selective degeneration of dopamine neurons in the substantia nigra pars compacta, which leads to bradykinesia, muscular rigidity, resting tremor, and postural instability.…”

Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

“…Decreased EAAT2 expression has been reported in animal models of PD, including the 6-hydroxydopaminelesioned PD model and the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated mouse model [145,146]. Recently, growing evidence shows ceftriaxone has beneficial effects in PD animal model, including the prevention of motor dysfunction, neuronal death, and PD related memory deficits [147][148][149][150][151][152]. EAAT2 has the potential as a target for PD therapy.…”

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

“…Parawixin 1, a molecule capable of augmenting the function of astrocyte glutamate transporter EAAT2, protected retinal neurons from ischemic degeneration (Fontana et al , 2007; Fontana et al , 2003). Beta-lactam antibiotics boosted glutamate uptake by astrocytes, enhancing neuroprotection in models of stroke and amyotrophic lateral sclerosis (Leung et al , 2012). Owing to the fact that AEG-1 intracellular localization is an important determinant of its functional outcome, future studies should be directed towards understanding the nucleolar functions of AEG-1, especially in the context of oxidative stress and aging.…”