Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

Bello, Fabio Del; Giannella, Maddalena; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma

doi:10.3390/biom9040142

Cited by 24 publications

(13 citation statements)

References 354 publications

(389 reference statements)

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“…So far, several reviews have been published that gathered information about the advances in the development of selective ligands [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Hamilton et al published a complex review that collects information about the rational drug design studies performed using QSAR, molecular docking, molecular dynamics and pharmacophore modeling, that were applied in the development of drugs against PD [ 52 ].…”

Section: Computational Approaches Used In the Development Of Novel Drugs Against Parkinson’s Diseasementioning

confidence: 99%

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

et al. 2021

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Parkinson’s disease is a progressive neurodegenerative disorder characterized by the death of nerve cells in the substantia nigra of the brain. The treatment options for this disease are very limited as currently the treatment is mainly symptomatic, and the available drugs are not able to completely stop the progression of the disease but only to slow it down. There is still a need to search for new compounds with the most optimal pharmacological profile that would stop the rapidly progressing disease. An increasing understanding of Parkinson’s pathogenesis and the discovery of new molecular targets pave the way to develop new therapeutic agents. The use and selection of appropriate cell and animal models that better reflect pathogenic changes in the brain is a key aspect of the research. In addition, computer-assisted drug design methods are a promising approach to developing effective compounds with potential therapeutic effects. In light of the above, in this review, we present current approaches for developing new drugs for Parkinson’s disease.

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Section: Computational Approaches Used In the Development Of Novel Drugs Against Parkinson’s Diseasementioning

confidence: 99%

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

et al. 2021

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“…The latter possibility is conceivable as >95% of striatal neurons are inhibitory and tightly coupled and so, like M1, may be capable of sustaining high-frequency gamma oscillations. Finally, it is conceivable that focal gamma is mediated by dopamine D4 receptors in the basal ganglia (Bello et al, 2019) as D4R-mediated gamma oscillations have been observed in the hippocampus (Andersson et al, 2012).…”

Section: Focal 80-hz Gamma Following High-dose L-dopa Primingmentioning

confidence: 99%

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

Bartlett

Sherman

et al. 2020

Preprint

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L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson′s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub- anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured locomotor and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, high-dose priming triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed under the low-dose procedure despite clear evidence of LID, indicating that 80- Hz oscillations are not an exclusive signature of LID. Instead, the low-dose procedure resulted in the weeks-long gradual emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L- DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID, but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine′s therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures associated with the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD, and as we identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

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“…В качестве средства, способного корригировать леводопа-индуцированную дискинезию, предложено еще одно производное морфолина -VU6004461. Его механизм действия заключается в непосредственной активации D4-дофаминовых рецепторов [65], что роднит его с рядом противопаркинсонических препаратов, включающим прамипексол, ропинирол, перголид и бромокриптин [66]. У мышей с 6-ГД-моделью БП VU6004461 в дозах 10 и 20 мг/кг значительно уменьшал выраженность аномальных непроизвольных движений, связанных с приемом леводопы [67].…”

Section: Vu6004461unclassified

Morpholine derivatives as potential agents for neurological manifestations of nervous system diseases

et al. 2020

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Diseases of the nervous system, especially those of vascular, traumatic, and neurodegenerative nature, are characterized by high prevalence, disability and mortality rates, and therefore have a particularly big medical and social impact. Currently, pharmacotherapy options for these diseases are limited to a relatively small number of clinically proven drugs, which is largely due to the difficulties associated with the translation of preclinical studies results. This explains the essential importance of discovering and developing new drugs, both effective and safe, that could be used to reduce clinical manifestations of neurological disorders. The present review is aimed to give a detailed account of several biologically active derivatives of morpholine, a six-membered heterocyclic compound. As demonstrated by a number of in vitro and in vivo studies using cell and animal models, morpholine derivatives should be considered viable drug candidates for a broad range of neurological diseases.

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Receptor Ligands as Helping Hands to L-DOPA in the Treatment of Parkinson’s Disease

Cited by 24 publications

References 354 publications

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

Current Approaches and Tools Used in Drug Development against Parkinson’s Disease

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

Morpholine derivatives as potential agents for neurological manifestations of nervous system diseases

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