Pharmacological Interventions in Parkinsonian Models

Parkinson’s disease is characterised by the progressive loss of dopaminergic neurons within the substantia nigra and the resultant depletion of striatal dopamine. Preclinical models, most commonly induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA), recapitulate the motor deficits and some non-motor features of the human disorder. Pharmacological interventions in these models have evolved beyond symptomatic dopamine replacement to include modulators of glutamatergic, serotonergic and glycinergic neurotransmission, as well as agents targeting receptor allostery. Levodopa (L-DOPA) remains the cornerstone of symptomatic therapy but is limited by motor complications such as dyskinesia. Adjunctive therapies aim to extend the benefit of L-DOPA and to prevent or attenuate dyskinesias by engaging novel targets: inhibitors of glycine transport, positive allosteric modulators of metabotropic glutamate receptors and inverse agonists at serotonin 5-HT2A/2C receptors. These approaches seek not only to restore motor function but also to mitigate long-term complications, bridging the gap between rodent studies and clinical application. Recent work has further refined our understanding of receptor-level adaptations and the interplay between excitatory and inhibitory circuits in basal ganglia models, informing strategies for neuroprotection and functional recovery.

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Pharmacological Interventions in Parkinsonian Models publication trend

The graph below shows the total number of articles in pharmacological interventions in parkinsonian models across all publications each year (not limited to Nature Index journals).

Technical terms

L-DOPA: A metabolic precursor of dopamine used as the primary symptomatic treatment in Parkinson’s models and patients.

Dyskinesia: Involuntary, hyperkinetic movements that emerge as a complication of chronic L-DOPA therapy.

MPTP: A lipophilic neurotoxin that crosses the blood–brain barrier and selectively ablates nigrostriatal dopaminergic neurons.

6-OHDA: A hydroxylated dopamine analogue used to lesion the nigrostriatal pathway in rodent models.

Positive allosteric modulator: A compound that binds to a receptor’s allosteric site, enhancing the response to its endogenous ligand without directly activating the orthosteric site.

Inverse agonist: A ligand that stabilises a receptor in its inactive conformation, reducing its constitutive activity.

References

1. Effect of glycine transporter 1 inhibition with bitopertin on parkinsonism and L-DOPA induced dyskinesia in the 6-OHDA-lesioned rat. European Journal of Pharmacology (2022).
2. Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain. Journal of Chemical Neuroanatomy (2024).
3. Effect of the mGlu2 positive allosteric modulator biphenyl‐indanone A as a monotherapy and as adjunct to a low dose of L‐DOPA in the MPTP‐lesioned marmoset. European Journal of Neuroscience (2024).
4. The 5‐HT2A/2C inverse agonist nelotanserin alleviates L‐DOPA‐induced dyskinesia in the MPTP‐lesioned marmoset. European Journal of Neuroscience (2023).