A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

Muddapu, Vignayanandam Ravindernath; Vijayakumar, K.; Ramakrishnan, Keerthiga; Chakravarthy, V. Srinivasa

doi:10.3389/fnins.2022.797127

Cited by 7 publications

(4 citation statements)

References 154 publications

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“…These preclinical data, as well as the approved use of this combination as a standard-of-care for Parkinson’s disease (PD) support further exploration of L-DOPA + carbidopa combination for GCPII inhibition; however, we advanced D-DOPA for further evaluation versus L-DOPA for the following reasons. First, chronic use of L-DOPA/carbidopa therapy is associated with neurotoxicity in preclinical models [ 49 , 50 ]; mechanistic studies show that L-DOPA neurotoxicity is related to dopamine generation and is not phenocopied with D-DOPA [ 51 ]. In PD patients, its long-term use is shown to cause disabling motor effects such as levodopa-induced dyskinesias (LIDs) and motor fluctuations in at least two thirds of patients [ 52 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

et al. 2022

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Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.

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Section: Resultsmentioning

confidence: 99%

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

et al. 2022

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“…On the other hand, these activated microglia seem to progress even under the medication of mainly levodopa/DCI. While previous in vitro studies indicated that levodopa acts as neuroprotective agent, several reports suggested that the high dose and long-term levodopa therapy might be harmful by a mechanism that probably involves oxidative stress 30 . In this study, our PD patients are at the early-stage and their motor symptom were well controlled under the therapy with mild dose of levodopa/DCI and/or small amount of amantadine.…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation following anti-parkinsonian drugs in early Parkinson’s disease: a longitudinal PET study

Terada,

Bunai,

Hashizume

et al. 2024

Sci Rep

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The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson’s disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1–2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide+) that did and one (zonisamide−) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([11C]DPA713 PET), dopamine transporter availability ([11C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [11C]DPA713 (BPND) and [11C]CFT (SUVR) were compared with normal data and between the zonisamide+ and zonisamide− PD groups. The cerebral [11C]DPA713 BPND increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide+ group with the zonisamide− group showed lower levels in the cerebral [11C]DPA713 BPND in the zonisamide+ group. While the striatal [11C]CFT SUVR decreased longitudinally, the [11C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide+ group. A significant annual increase in attention score were found in the zonisamide+ group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.

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“…The oxidation of L-DOPA can generate ROS and DAQs [71,72]. Furthermore, long-term replenishment of L-DOPA to maintain higher DA levels in dopaminergic neurons to alleviate PD symptoms may accelerate DA neurodegeneration and disease progression in PD patients [73,74]. The sites of action of these medications are summarized in Figure 1.…”

Section: Current Therapeutic Strategiesmentioning

confidence: 99%

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson’s Disease

Yi,

Tan,

Zhou

2024

IJMS

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There are currently no disease-modifying therapies for Parkinson’s disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients’ brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.

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A Multi-Scale Computational Model of Levodopa-Induced Toxicity in Parkinson's Disease

Cited by 7 publications

References 154 publications

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

Neuroinflammation following anti-parkinsonian drugs in early Parkinson’s disease: a longitudinal PET study

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson’s Disease

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