Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling

Stopera, C. J.; Bartlett, M. J.; Bernard, K.; Conklin, R.; Singh, S.; Frye, J.; Madhavan, L.; Doyle, K. P.; Sherman, S. J.; Steece-Collier, K.; Falk, T.

doi:10.64898/2026.10.28.762430

bioRxiv · 10.64898/2026.10.28.762430

Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling

Stopera, C. J.·Bartlett, M. J.·Bernard, K.·Conklin, R.·Singh, S.·Frye, J.·Madhavan, L.·Doyle, K. P.·Sherman, S. J.·Steece-Collier, K.·Falk, T.

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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.

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Stopera, C. J., Bartlett, M. J., Bernard, K., Conklin, R., Singh, S., Frye, J., Madhavan, L., Doyle, K. P., Sherman, S. J., Steece-Collier, K., Falk, T.. 2026-10-29. Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling. https://doi.org/10.64898/2026.10.28.762430

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