Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling
Carolyn J Stopera, Mitchell J Bartlett, Kelsey Bernard, Rachel Conklin, Sansita Singh, Jennifer Frye, Lalitha Madhavan, Kristian Doyle, Scott J Sherman, Kathy Steece-Collier, Torsten Falk
bioRxiv October 29, 2026 preprint DOI: 10.64898/2026.10.28.762430 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study |
|---|---|
| Population | Rats in a progressive 6-hydroxydopamine (6-OHDA) model of Parkinson's disease |
| Interventions | Ketamine ANA-12 |
| Dose | 20 mg/kg, i.p. |
| Topics | Esketamine Ketamine |
| Key points | Ketamine (20 mg/kg, i.p.) given before striatal 6-OHDA provided near complete protection against parkinsonian motor deficits despite only modest preservation of striatal tyrosine hydroxylase (about 50-60% loss). The authors report that this protection was not mediated by TrkB receptors, as ketamine plus the TrkB antagonist ANA-12 did not block the effect, and they conclude that complex mechanisms underlie the neuroprotective activity of low-dose ketamine. |
Abstract
Treatment with low-dose ketamine is neuroprotective in rodent models of acute damage, while high doses of ketamine can be neurotoxic. Our group has previously shown that sub-anesthetic ketamine treatment leads to long-term reduction of L-DOPA-induced dyskinesia (LID) via brain-derived neurotrophic factor (BDNF)-signaling in a rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this report, we investigated if sub-anesthetic ketamine is also neuroprotective in a progressive 6-OHDA model of PD via neurotrophic action through the tropomyosin receptor kinase B (TrkB) receptor. We demonstrated that ketamine-treatment (20 mg/kg, i.p.) prior to striatal administration of the neurotoxin 6-OHDA is neuroprotective, providing near complete protection against development of parkinsonian motor deficits. This robust behavioral efficacy occurred in the presence of only modest preservation of tyrosine hydroxylase (TH) striatal levels (~50-60% loss). Interestingly, based on data from an additional cohort treated with ketamine and ANA-12 (TrkB antagonist) we found that the neuroprotective effects of ketamine are not mediated by TrkB receptors. Semi-quantitative western analysis showed that the relative tyrosine hydroxylase content in the striatum was not significantly increased in ketamine-treated rats compared to vehicle. Unbiased stereology of dopamine neurons in the substantia nigra pars compacta (SNc) revealed no significant differences between any of the groups. The role of BDNF was evaluated with in situ hybridization for RNA of BDNF and TrkB. While BDNF expression was not changed, co-administration of ketamine and ANA-12 led to a significant decrease in TrkB receptor expression compared to ketamine-only on the lesioned but not the intact hemisphere in the SNc. In conclusion, we show that ketamine at the low dose currently pursued for therapeutic benefit for LID led to robust behavioral motor improvement in this rodent PD degeneration model, yet these protective effects were not driven by neurotrophic BDNF-signaling, indicating complex mechanisms are underlying neuroprotective activities of low-dose ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |