The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis

Abstract

N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling. Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84. Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and-activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-κB activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished. In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy.

Correlates of Post-Stroke Brain Plasticity, Relationship to Pathophysiological Settings and Implications for Human Proof-of-Concept Studies

“…The intrinsic capacity of brain repair can be efficiently stimulated by exogenous therapeutic interventions, e.g., by physical exercise, delivery of growth factors, cell-based biologicals or pharmacological compounds, which in rodent and primate models of stroke were shown to enhance neurological recovery (Bacigaluppi et al, 2009 ; Reitmeir et al, 2011 , 2012 ; Jaeger et al, 2015 ; Wang et al, 2016 ). Neurological recovery in the experimental setting can be defined as regain of lost function of the paretic limb as compared to a baseline defined previous to the stroke, which should not be confused with neurological compensation (Murphy and Corbett, 2009 ), in which other parts of the limbs (e.g., shoulder or the non-paretic limb) are recruited to complete a task.…”

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

“…Flupirtine is well known for its significant powerful anti-oxidative, anti-apoptotic, and neuroprotective effects in vitro and in vivo. The effectiveness of the chosen daily dose of flupirtine (30 mg/kg per os) has been demonstrated in testing for anti-nociceptive, anticonvulsant, and anti-apoptotic activity in rodents [ 23 , 24 , 25 , 26 , 27 ]. This study is the first to evaluate the use of flupirtine as potential treatment for CLN3 disease in an animal model, i.e., in vivo.…”

Kcnq2/Kv7.2 controls the threshold and bihemispheric symmetry of cortical spreading depolarization

“…Retigabine inhibits SD in mild, but not severe oxygen-glucose deprivation (OGD) model. Kv7 activators have been shown to reduce neuronal damage following experimental ischemia, where SD could potentially contribute to progression of the lesion 46,47 . We examined whether the Kv7 activator retigabine can also inhibit SD generated during the experimental in vitro ischemia model of oxygen- Figure 7.…”

“…We showed that retigabine could delay SD onset following submaximal OGD stimulation. Interestingly, Kv7.2 activators are neuroprotective in experimental ischemia and brain trauma studies 46,47,51,59,60 , and the anti-SD properties of the activator may contribute to these neuroprotective effects. It should be noted that only a relatively high, sedating, drug concentration effectively inhibited SD, and the drug may therefore be of limited prophylactic utility.…”