Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy

Abstract

Antiepileptic drugs (AEDs) have repeatedly shown inconsistent and almost contradictory effects on the neurocognitive system, from substantial impairments in processing speed to the noticeable improvement in working memory and executive functioning. Previous studies have provided a novel insight into the cognitive improvement by bumetanide as a potential antiepileptic drug. Through the current investigation, we evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on the brain microstructural organization as a probable underlying component for cognitive performance. Microstructure assessment was completed using SPM for the whole brain assay and Freesurfer/TRACULA for the automatic probabilistic tractography analysis. Primary cognitive operations including selective attention and processing speed, working memory capacity and spatial memory were evaluated in 12 patients with a confirmed diagnosis of refractory epilepsy. Participants treated with bumetanide (2 mg/ day) in two divided doses as an adjuvant therapy to their regular AEDs for 6 months, which followed by the re-assessment of their cognitive functions and microstructural organizations. Seizure frequency reduced in eight patients which accompanied by white matter reconstruction; fractional anisotropy (FA) increased in the cingulum-cingulate gyrus (CCG), anterior thalamic radiation (ATR), and temporal part of the superior longitudinal fasciculus (SLFt) in correlation with the clinical response. The voxel-based analysis in responder patients revealed increased FA in the left hippocampus, right cerebellum, and right medial temporal lobe, while mean diffusivity (MD) values reduced in the right occipital lobe and cerebellum. Microstructural changes in SLFt and ATR accompanied by a reduction in the error rate in the spatial memory test. These primary results have provided preliminary evidence for the effect of bumetanide on cognitive functioning through microstructural changes in patients with drug-resistant epilepsy.

Efficacy and Safety of Bumetanide in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Clinical Trial

“…While the concentration of the bumetanide remains low in the brain after systemic administration [23], recent investigations indicated that bumetanide can control some aspects of neurological and neuropsychological disorders [24]. Prior studies have demonstrated that bumetanide improves ASD behaviours as assessed by the Childhood Autism Rating Scale (CARS) and CGI in children [17].…”

“…Interestingly, a recent report has shown downregulation of Na-K-Cl cotransporter 1(NKCC1) protein following bumetanide treatment that may be responsible for its antiepileptic effects [35]. Also, another investigation indicated that bumetanide is e cient on the reduction of seizure frequency in adult patients with temporal lobe epilepsy (TLE) through the microstructural reorganization that mostly affects the epileptic regions [15,24]. Even though bumetanide concentration in the brain environment remains low after administration, investigations on Huntington and Down's model indicated that restoring the inhibitory function of GABA by bumetanide might contribute in memory improvement via inducing modi cations in synaptic plasticity patterns [36,37].…”

Inhibition of the NKCC1/NF-κB Signaling Pathway Decreases Inflammation and Improves Brain Edema and Nerve Cell Apoptosis in an SBI Rat Model

“…The primary function of NKCC1 is to regulate the entry of Na + , K + , Cl – , and water into cells to regulate the transfer and invasion of inflammatory mediators and other related factors, which can lead to brain edema, inflammation, and secondary brain damage. NKCC1 is closely related to cerebral hemorrhage ( Wu et al, 2020a ), stroke ( Wu et al, 2020b ), epilepsy ( Gharaylou et al, 2019 ; Zhang et al, 2020b ), traumatic brain injury ( Sudhakar et al, 2019 ), and other brain diseases. However, the activity of NKCC1 is mainly regulated by the STE20-related proline/alanine kinase (SPAK)/oxidative stress response 1 (OSR1) signaling pathway.…”

Pharmacological tools to target NKCC1 in brain disorders

“…Indeed, fMRI was used to assess brain microstructural abnormalities. In particular, alteration of diffusion tensor imaging indices correlated with downregulation of KCC2 in PMBCs from TLE subjects, and this alteration was rescued by bumetanide treatment [140,141].…”