Eltoprazine prevents levodopa‐induced dyskinesias by reducing striatal glutamate and direct pathway activity

Paolone, Giovanna; Brugnoli, Alberto; Arcuri, Ludovico; Mercatelli, Daniela; Morari, Michele

doi:10.1002/mds.26326

Cited by 52 publications

(68 citation statements)

References 70 publications

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“…In these days, various approaches using 5-HT 1A agonists target mainly motor fluctuation in PD [138-142, 161-167] (Table 1). Eltoprazine, a selective 5-HT 1A and 5-HT 1B agonist, is currently being tested in clinical trials for motor complications derived from dopaminergic therapy in PD [140, 141].…”

Section: Serotonin 1a (5-ht1a) Receptors On Astrocytes As a Novel Tarmentioning

confidence: 99%

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Miyazaki

Asanuma²

2016

CMC

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Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease-modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.

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Section: Serotonin 1a (5-ht1a) Receptors On Astrocytes As a Novel Tarmentioning

confidence: 99%

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Miyazaki

Asanuma²

2016

CMC

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“…11 Therefore, increased GLT-1 and glutamate uptake may reduce LID severity by reducing excess glutamatergic neurotransmission, as seen with observations showing reduced LID in association with reduced glutamate release. 49,50 To the converse, others have not reported any difference in striatal glutamate concentrations in the lesioned nigrostriatal pathway, 10,74,75 which may be attributed to timedependent changes in release and uptake and their contributions to extracellular glutamate concentration and when these determinations were made after lesion induction or the lesion site. 4,5,40,75 As a result, postlesion time points and lesion topography are relevant metrics for timing therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…35,47,48 The pharmacological-based reduction of striatal or nigral glutamate efflux may reduce LID severity. [49][50][51] GLT-1 is a primary glial glutamate transporter responsible for clearing synaptic glutamate 52 and may be involved in neurodegenerative processes. 11,[15][16][17][18] Ceftriaxone, a beta-lactam antibiotic, can increase GLT-1 expression with >5 consecutive daily injections.…”

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confidence: 99%

Ceftriaxone reduces L‐dopa–induced dyskinesia severity in 6‐hydroxydopamine parkinson's disease model

et al. 2017

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Background Increased extracellular glutamate may contribute to L-DOPA induced dyskinesia, a debilitating side effect faced by Parkinson’s disease patients 5–10 years after L-DOPA treatment. Therapeutic strategies targeting post-synaptic glutamate receptors to mitigate dyskinesia may have limited success due to significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at time of nigrostriatal lesion, can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. Here, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to L-DOPA, could reduce L-DOPA-induced dyskinesia in an established dyskinesia model. Methods Ceftriaxone (200 mg/kg, i.p., once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7–13) and continued every other week (days 21–27, 35–39) until the end of the study (day 39 post-lesion, 20 days of L-DOPA). Results Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic L-DOPA treatment. Partial recovery of motor impairment from nigrostriatal lesion by L-DOPA was unaffected by ceftriaxone. The ceftriaxone-treated L-DOPA group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different compared to the L-DOPA alone group. Conclusions Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during L-DOPA, may reduce dyskinesia severity without affecting L-DOPA efficacy or reduction of striatal tyrosine hydroxylase loss.

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“…In stress-induced hyperthermia test, eltoprazine failed to demonstrate any effect (Zethof et al 1995), a finding somewhat contradictory to the results of the present study, where dose-dependent hypothermia was observed. Eltoprazine also abolished stress-induced ultrasonic vocalization in adult rats (Sanchez 1993) Eltoprazine produced dose-dependent hypothermia with a minimal effective dose of 1 mg/kg, which seems to be within range decreasing weight gain but slightly higher than doses reported to exert antidyskinetic effects (0.3 mg/kg) (Paolone et al 2015). Hyperthermic activity of 5-HT1A ligands seems to correlate with the potency and the intrinsic activity at the 5-HT1A receptor (Millan et al 1993).…”

Section: Discussionmentioning

confidence: 99%

Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse‑effect potential

Gravius¹,

Dekundy²,

Vanaga³

et al. 2017

Acta Neurobiologiae Experimentalis

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Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L-DOPA-induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study.Given for 2 weeks either as infusion or as twice-daily treatment, eltoprazine produced a decrease in food intake and body weight at doses leading to 200-500 nM plasma concentrations.In the elevated plus maze eltoprazine increased anxiety-like behavior. On the other hand, it induced a clear-cut anxiolytic effect in context fear conditioning test starting at ca. 0.3 mg/kg, and failed to produce any significant effect in fear potentiated startle test.Regarding adverse effects, eltoprazine was found to produce hypothermia starting from 1 mg/kg. At similar doses it also increased locomotion in the open field. However, eltoprazine failed to affect acquisition in context fear conditioning paradigm, which may indicate lack of its detrimental effect on learning at the doses tested (i.e., up to 5 mg/kg).In summary, effects of eltoprazine in different anxiety tests were equivocal while its effect on body weight seems robust and requires further investigation. It is to be determined whether these effects can be expected at the doses free of adverse effects.

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Eltoprazine prevents levodopa‐induced dyskinesias by reducing striatal glutamate and direct pathway activity

Cited by 52 publications

References 70 publications

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease

Ceftriaxone reduces L‐dopa–induced dyskinesia severity in 6‐hydroxydopamine parkinson's disease model

Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse‑effect potential

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