Preclinical evidence in support of repurposing sub-anesthetic ketamine as a treatment for L-DOPA-induced dyskinesia

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Pharmacotherapy with L-DOPA remains the gold-standard therapy for PD, but is often limited by the development of the common side effect of L-DOPA-induced dyskinesia (LID), which can become debilitating. The only effective treatment for disabling dyskinesia is surgical therapy (neuromodulation or lesioning), therefore effective pharmacological treatment of LID is a critical unmet need. Here, we show that sub-anesthetic doses of ketamine attenuate the development of LID in a rodent model, while also having acute anti-parkinsonian activity. The long-term anti-dyskinetic effect is mediated by brain-derived neurotrophic factor-release in the striatum, followed by activation of ERK1/2 and mTOR pathway signaling. This ultimately leads to morphological changes in dendritic spines on striatal medium spiny neurons that correlate with the behavioral effects, specifically a reduction in the density of mushroom spines, a dendritic spine phenotype that shows a high correlation with LID. These molecular and cellular changes match those occurring in hippocampus and cortex after effective sub-anesthetic ketamine treatment in preclinical models of depression, and point to common mechanisms underlying the therapeutic efficacy of ketamine for these two disorders. These preclinical mechanistic studies complement current ongoing clinical testing of sub-anesthetic ketamine for the treatment of LID by our group, and provide further evidence in support of repurposing ketamine to treat individuals with PD. Given its clinically proven therapeutic benefit for both treatment-resistant depression and several pain states, very common co-morbidities in PD, sub-anesthetic ketamine could provide multiple therapeutic benefits for PD in the future.

Ketamine: Neuroprotective or Neurotoxic?

“…While NMDARs are broadly expressed in both excitatory and inhibitory neurons, the antidepressant-like effects of ketamine seem to require actions at inhibitory interneurons (iINs) (Miller et al, 2015;Widman and McMahon, 2018;Gerhard et al, 2020). As such, the "disinhibition hypothesis" posits that ketamine's antagonism of NMDARs on GABAergic iINs causes the disinhibition of downstream excitatory pyramidal neurons (PNs), resulting in activity-dependent synaptic plasticity (that requires protein synthesis) and antidepressant-like or neuroprotective effects (Miller et al, 2015;Widman and McMahon, 2018;Bartlett et al, 2020;Grieco et al, 2020). In support of this hypothesis, genetic deletions of GluN2B in iINs abolished the antidepressant effects of ketamine (Gerhard et al, 2020).…”

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

“…Given evidence that ketamine can reduce dyskinesias by ~50% regardless of L-DOPA dose, 6-7 mg/kg and 12 mg/kg (Bartlett et al, 2020(Bartlett et al, , 2016, we predicted that spectral signatures of LID would decrease after ketamine administration. Specifically, we hypothesized that ketamine administration would reduce the striatal broadband gamma activity we observed during LID in animals exposed to the 21-day low-dose priming procedure.…”

“…Ketamine exposure can induce neuroplastic changes that endure for weeks following a single exposure in rats (Li et al, 2010). Furthermore, a single 10-hour ketamine exposure can produce a weeks-long reduction in an animal model of LID (Bartlett et al, 2020(Bartlett et al, , 2016, suggesting that ketamine-induced neuroplastic changes contribute to reduced LID. To investigate this, we examined LID on-state spectral activity for the days prior to and following the first exposure to ketamine.…”

“…Prior work has shown that the long-term anti-dyskinetic effect of ketamine correlates with changes in dendritic spine density, specifically a reduction of multi-synaptic mushroom spines, in the striatum, yet changes in dendritic spines in the M1 had not been investigated in that study. And this effect of cortically-derived BDNF release can be blocked by systemically inhibiting BDNF-signaling (Bartlett et al, 2020).…”

“…A retrospective case study in PD patients receiving sub-anesthetic infusions of ketamine to treat pain showed reduced LID for up to one month (Sherman et al, 2016). Ketamine treatment can also reduce LID long-term in rodent models of established LID and of LID development (Bartlett et al, 2020(Bartlett et al, , 2016. These lasting effects may be due to ketamine's ability to modify oscillatory activity throughout the brain (Hunt and Kasicki, 2013;Ye et al, 2018).…”