Objective: To determine whether chronic IEM-1460 administration alters dyskinesia and perineuronal net (PNN)–parvalbumin interneuron (PV-IN) association in a 6-OHDA rat model of L-DOPA-induced dyskinesia (LID).

Background: LID is a motor complication of long-term L-DOPA treatment in Parkinson’s Disease. Corticostriatal maladaptive plasticity is considered one of the key mechanisms underlying LID pathophysiology [1]. In our recent work, we showed that changes in PNN–PV-IN association, marked by an increase in PNN-negative PV-INs in the dorsolateral striatum (DLS) and its projecting motor cortex (M1), may contribute to this maladaptive process [2]. Given the potential involvement of PV-IN-related remodeling in LID, IEM-1460, which blocks GluA2-lacking Ca²⁺-permeable AMPA receptors expressed predominantly by PV-positive fast-spiking INs in striatum and has been shown to reduce LID in rodent and primate models [3].

Method: Male Wistar rats with hemiparkinsonism induced by 6-OHDA injection into the right medial forebrain bundle received L-DOPA/benserazide (25/6.25 mg/kg, i.p.) alone (n=6) or in combination with IEM-1460 (3 mg/kg, i.p.) (n=6) for 15 days. In perfused brain tissues, double immunofluorescence staining for WFA and PV was performed. Cell densities of total WFA⁺, total PV⁺ and subgroups, together with fluorescence intensities of total WFA⁺ and PV⁺, were evaluated in the DLS and M1 using confocal images.

Results: There was no significant difference in total AIMs scores between the LID and IEM-1460-treated groups, except that axial AIMs scores on day 1 were lower in the IEM-1460 group (p=0.02). In the DLS, total PV⁺ (p=0.0002) and WFA^–/PV⁺ (p<0.0001) cell densities were significantly reduced in the IEM-1460 group. Similarly, in M1, total PV⁺ and WFA^–/PV⁺ cell densities were significantly lower in the IEM-1460 group than in the LID group (all p<0.0001). Total WFA⁺ and PV⁺ fluorescence intensities were lower in the IEM-1460 group in both regions (all p<0.0001).

Conclusion: These findings suggest that, although IEM-1460 had limited behavioral effects, it modulated PNN–PV-IN association in the corticostriatal motor axis. This modulation was particularly evident in PNN-negative PV-IN subpopulations. Our results support the idea that PNN-related PV-IN diversity may contribute to the pathophysiology of LID.

References: 1. Cenci, M.A.; Jörntell, H.; Petersson, P. On the neuronal circuitry mediating L-DOPA-induced dyskinesia. Journal of Neural Transmission 2018, 125, 1157-1169.
2. Bilbay, N. T.; Tel, B. C.; Akkus, G.; Cakir-Aktas, C.; Solakoglu, T.; Yalcin-Cakmakli, G.; Elibol, B. Remodeling of Perineuronal Nets in the Striato-Cortical Axis in L-DOPA-Induced Dyskinesia Rat Model. International Journal of Molecular Sciences 2025, 26(23), 11726.
3. Kobylecki, C.; Crossman, A. R.; Ravenscroft, P. Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson’s disease and L-DOPA-induced dyskinesia. Experimental neurology 2013, 247, 476-484.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-chronic-iem-1460-treatment-on-perineuronal-net-parvalbumin-interneuron-association-in-l-dopa-induced-dyskinesia/