Preventing neuronal edema increases network excitability after traumatic brain injury

Sawant-Pokam, Punam A.; Vail, Tyler; Metcalf, Cameron S.; Maguire, Jamie; McKean, Thomas O.; McKean, Nick O.; Brennan, K. C.

doi:10.1172/jci134793

Cited by 32 publications

(22 citation statements)

References 88 publications

(156 reference statements)

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“…NKCC1 upregulation and/or KCC2 downregulation were reported in brains of rodents after traumatic brain injury (TBI; induced by weight-drop, controlled cortical impact, or closedhead cortical injury) [68][69][70][71][72][73], spinal cord injury (SCI), peripheral nerve injury (PNI), and chronic and acute neuropathic pain (induced by chemicals, SCI, PNI, or bone cancer) [74][75][76][77][78][79][80][81][82][83][84] (but see [85]) (Table 1). Bumetanide decreased the inflammatory response, neuronal damage, and edema formation in TBI models [68,69,71,72,86] (but see [87]). Moreover, it also reduced edema, tissue destruction, and spasticity, rescued reflexes, and showed an analgesic action in PNI, SCI, and neuropathic pain models [74][75][76]78,83] (Table 2).…”

Section: Insult-induced Neurological Disordersmentioning

confidence: 99%

Pharmacological tools to target NKCC1 in brain disorders

Savardi

Borgogno

Vivo

et al. 2021

Trends in Pharmacological Sciences

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The chloride importer NKCC1 and the chloride exporter KCC2 are key regulators of neuronal chloride concentration. A defective NKCC1/KCC2 expression ratio is associated with several brain disorders. Preclinical/clinical studies have shown that NKCC1 inhibition by the United States FDA-approved diuretic bumetanide is a potential therapeutic strategy in preclinical/clinical studies of multiple neurological conditions. However, bumetanide has poor brain penetration and causes unwanted diuresis by inhibiting NKCC2 in the kidney. To overcome these issues, a growing number of studies have reported more brain-penetrating and/or selective bumetanide prodrugs, analogs, and new molecular entities. Here, we review the evidence for NKCC1 pharmacological inhibition as an effective strategy to manage neurological disorders. We also discuss the advantages and limitations of bumetanide repurposing and the benefits and risks of new NKCC1 inhibitors as therapeutic agents for brain disorders. Neuronal Cl homeostasis: role in brain function and disordersIn neurons, the sodium (Na + )-potassium (K + )-Cltransporter isoform 1 (NKCC1, SLC12A2) and the K + -Cltransporter isoform 2 (KCC2, SLC12A5) [1] are key regulators of intracellular chloride concentration ([Cl -] i ). In the central nervous system (CNS), NKCC1 functions as a Climporter, and is highly expressed in immature neurons during early development [2]. Conversely, KCC2 expression is relatively low in early development (resulting in a high NKCC1/KCC2 ratio), increases during the postnatal period, and is more highly expressed in mature neurons (resulting in a low NKCC1/KCC2 ratio; Box 1). The fine regulation of [Cl -] i by NKCC1 and KCC2 is essential for brain development, including cell proliferation and apoptosis, and neuronal migration and maturation [3]. Moreover, NKCC1 and KCC2 are key for neuronal synaptic plasticity (see Glossary) and for maintaining a proper excitatory/inhibitory balance, which is fundamental for brain functions [3].A defective NKCC1/KCC2 expression ratio is often associated with several neurological and psychiatric disorders [4]. In particular, a large and growing body of literature reporting preclinical and clinical studies has shown that upregulation of NKCC1 and/or downregulation of KCC2 (resulting in an increased NKCC1/KCC2 ratio) underlie neurodevelopmental, insult-induced neurological, and neurodegenerative disorders [4] (Box 1; see Outstanding questions). Restoring neuronal [Cl -] i by inhibiting NKCC1 with bumetanide (an unselective NKCC1 inhibitor) was the first proof of concept for NKCC1 as a valuable target for several neurological conditions in preclinical (animal models) and clinical studies (patients) [5,6] (see Outstanding questions). Bumetanide is an FDAapproved thick ascending loop (TAL) of Henle diuretic, which acts by inhibiting the kidney transporter NKCC2. Due to its potent diuretic effect, bumetanide is currently indicated only to treat edema and swelling caused by congestive heart failure, acute pulmonary congestion, and hepatic an...

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Section: Insult-induced Neurological Disordersmentioning

confidence: 99%

Pharmacological tools to target NKCC1 in brain disorders

Savardi

Borgogno

Vivo

et al. 2021

Trends in Pharmacological Sciences

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“…Aquaporin-4 (AQP4) is expressed abundantly in glia, particularly astrocytic endfoot processes abutting blood vessels, ependymal cells, and the subarachnoid space lining [55,56] ("Brain Cell Swelling with Osmotic Shifts" section). AQP4 expression is upregulated in several pathologies, including ischemia and TBI [57], and is known to significantly mediate cerebral edema through glial swelling [8,57,58]. Solenov et al [57] observed reduced astrocytic swelling in AQP4-deficient mouse models.…”

Section: Questioning Classic Assumptions Of Osmotic Theorymentioning

confidence: 99%

“…Inhibiting the cotransporters NKCC1 and KCC2 (chloride transporters), anion exchange protein (AE3), and monocarboxylate transporter (MCT2) reduces dendritic beading in vivo, indicating that pronounced ion displacement during SD leads to transmembrane solute imbalances, dramatically reducing neuronal water influx in the seconds and minutes post-SD [ 31 ] (“ Transport (Carrier) Proteins and Neuronal Swelling ” section). Over the longer-term, the NKCC1 blocker bumetanide reduces cerebral edema in vivo post-TBI by decreasing cotransported water influx from stressed neurons [ 58 ]. Is this swelling osmotically driven?…”

Section: Brain Cell Swelling and Ischemiamentioning

confidence: 99%

“…This excitability arises at the cellular level and is not a result of brain compression. Over many hours following stroke or TBI, neurons may join astrocytes in swelling, but these neurons display lowered excitability [ 58 , 99 ].…”

Section: Brain Cell Swelling and Ischemiamentioning

confidence: 99%

“…These fields display reduced excitation electrophysiologically (not shown) [ 99 ]. Similarly, adjacent to a TBI lesion, swollen neurons are observed in cortical regions exhibiting reduced excitability when patch-clamped [ 58 ]. So, ischemic edema swells neurons and astrocytes as well as reducing excitability over many hours or even days.…”

Section: Brain Cell Swelling and Ischemiamentioning

confidence: 99%

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Neuronal Swelling: A Non-osmotic Consequence of Spreading Depolarization

Hellas

Andrew

2021

Neurocrit Care

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An acute reduction in plasma osmolality causes rapid uptake of water by astrocytes but not by neurons, whereas both cell types swell as a consequence of lost blood flow (ischemia). Either hypoosmolality or ischemia can displace the brain downwards, potentially causing death. However, these disorders are fundamentally different at the cellular level. Astrocytes osmotically swell or shrink because they express functional water channels (aquaporins), whereas neurons lack functional aquaporins and thus maintain their volume. Yet both neurons and astrocytes immediately swell when blood flow to the brain is compromised (cytotoxic edema) as following stroke onset, sudden cardiac arrest, or traumatic brain injury. In each situation, neuronal swelling is the direct result of spreading depolarization (SD) generated when the ATP-dependent sodium/potassium ATPase (the Na+/K+ pump) is compromised. The simple, and incorrect, textbook explanation for neuronal swelling is that increased Na+ influx passively draws Cl− into the cell, with water following by osmosis via some unknown conduit. We first review the strong evidence that mammalian neurons resist volume change during acute osmotic stress. We then contrast this with their dramatic swelling during ischemia. Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia.

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