**2.2 Bumetanide**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

**82**

**Name of drug** Angiotensin receptor

blockers

Amantadine

**Table 1.** *List of repurposed drugs in neurological disease.*

Antiviral

Parkinson's disease

N-methyl-D-aspartate

(NMDA)

Anticholinergic

II.

Activating the dopamine system in several preclinical data demonstrate

Chronic traumatic brain

injury

**Original indication**

Essential hypertension

Renal disease

Diabetes

**Novel indication**

Alzheimer's disease

Episodic migraine

**Target** AT1 receptor

I. II.

Alleviating AD in epidemiological studies and RCTs

I.Improving motor symptoms in a female PD patient

Reducing Aβ accumulation and aggregation in vivo

Angiotensin II

**Summarization of evidence**

As a potent diuretic agent, bumetanide, which is mainly employed to cure liver disease, heart failure, and various kinds of stubborn edema in clinic [27], is a specific inhibitor of Na<sup>+</sup> -K<sup>+</sup> -2Cl<sup>−</sup> cotransporter isoform 1 (NKCC1) [28]. Mechanically, NKCC1 significantly modulates the content of intracellular Cl<sup>−</sup>. Upregulation of NKCC1 leads to elevation of intracellular concentration of Cl<sup>−</sup>, which is associated with pathogenesis of neurological diseases. It has been unequivocally proven that many of the available drugs have anti-seizure potential via activating GABAAmediated hyperpolarization due to accumulation of neuronal Cl<sup>−</sup> [29]. Indeed, current investigations have confirmed that bumetanide exerts antiepileptic effect via switching the GABA-mediated inhibitory postsynaptic potential in neurons from depolarization to hyperpolarization, resulting in decreased neuronal discharge [30, 31]. In addition, previous work reinforces that bumetanide can enhance the anticonvulsant effect of phenobarbital in hypoxic rats [32]. It suggests that the combination of phenobarbital and bumetanide may provide a promising therapeutic strategy for ceasing seizures in neonatal epilepsy and may increase the neuroprotective effect of hypothermia on asphyxiated newborns [33]. Persuasively, a current clinically pilot study further demonstrated that bumetanide, as a specific NKCC1 antagonist, considerably reduced seizure frequency in adult patients with temporal lobe epilepsy [34]. Additionally, as a consequence of a randomized controlled trial, bumetanide may also be effective for treatment of autism [35]. It should be considered that there are two obstacles for bumetanide treatment in neurological disorders [31, 36]. It has been shown that the highly potent diuretic effect of bumetanide can lead to hypokalemic alkalosis and the poor penetration into brain exists. This indicates that reuse of bumetanide in neurological diseases brings about opportunities and challenges in the future.
