Sustained elevation of cerebrospinal fluid glucose and lactate after a single seizure does not parallel with mitochondria energy production

Oses, Jean Pierre; Müller, Alexandre Pastoris; Strogulski, Nathan Ryzewski; Moreira, Júlia Dubois; Böhmer, Ana Elisa; Hansel, Gisele; Carteri, Randhall Bruce; Busnello, João Vicente; Kopczynski, Afonso; Rodolphi, Marcelo Salimen; Souza, Diogo O.; Portela, Luis Valmor

doi:10.1016/j.eplepsyres.2019.03.007

Cited by 13 publications

(14 citation statements)

References 49 publications

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“…[6][7][8][9] Lactate acts as a neuroprotectant in several disorders such as cerebral ischemia, brain injury, excitotoxicity, and mechanical insults. [6][7][8][9] Lactate acts as a neuroprotectant in several disorders such as cerebral ischemia, brain injury, excitotoxicity, and mechanical insults.…”

Section: Introductionmentioning

confidence: 99%

“…During epilepsy, lactate concentration increases in the hippocampus and cortex from ~2 mmol/L to ~6 mmol/L in the extracellular space. [6][7][8][9] Lactate acts as a neuroprotectant in several disorders such as cerebral ischemia, brain injury, excitotoxicity, and mechanical insults. [10][11][12] Lactate is an endogenous ligand for a recently discovered receptor HCA1 or GPR81, which is expressed in neurons, astrocytes, and blood vessels of various brain regions.…”

Section: Introductionmentioning

confidence: 99%

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Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Jorwal

Sikdar

2019

Epilepsia

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Objective: Much evidence suggests that the subiculum plays a significant role in the regulation of epileptic activity. Lactate acts as a neuroprotective agent against many conditions that cause brain damage. During epileptic seizures, lactate formation reaches up to ~6 mmol/L in the brain. We investigated the effect of lactate on subicular pyramidal neurons after induction of epileptiform activity using 4-aminopyridine (4-AP-0Mg 2+ ) in an in vitro epilepsy model in rats. The signaling mechanism associated with the suppression of epileptiform discharges by lactate was also investigated. Methods: We used patch clamp electrophysiology recordings on rat subicular neurons of acute hippocampal slices. Immunohistochemistry was used for demonstrating the expression of hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum. Results: Our study showed that application of 6 mmol/L lactate after induction of epileptiform activity reduced spike frequency (control 2.5 ± 1.23 Hz vs lactate 1.01 ± 0.91 Hz, P = .049) and hyperpolarized the subicular neurons (control −51.8 ± 1.9 mV vs lactate −57.2 ± 3.56 mV, P = .002) in whole cell patch-clamp experiments. After confirming the expression of HCA1 in subicular neurons, we demonstrated that lactate-mediated effect occurs via HCA1 by using its specific agonist. All values are mean ±SD. Electrophysiological recordings revealed the involvement of Gβγ and intracellular cAMP in the lactate-induced effect. Furthermore, current-clamp and voltage-clamp experiments showed that the G protein-coupled inwardly rectifying potassium (GIRK) channel blocker tertiapin-Q, negated the lactateinduced inhibitory effect, which confirmed that lactate application results in outward GIRK current. Significance: Our finding points toward the potential role of lactate as an anticonvulsant by showing lactate-induced suppression of epileptiform activity in subicular neurons. The study gives a different insight by suggesting importance of endogenous metabolite and associated signaling factors, which can aid in improving the present therapeutic approach for treating epilepsy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Jorwal

Sikdar

2019

Epilepsia

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“…Excess synaptic glutamate associated with excessive neuronal firing is taken up by astrocytes, and stimulates glycolytic activity in astrocytes and subsequent release of lactate into the extracellular space. 41,42 In addition, although somewhat controversial, evidence now suggests that lactate can be used as a fuel source for neurons. 38,39 Relative differences in brain volume, the number of neurons and supporting cells involved in the seizure and the mechanisms of seizure initiation or propagation between dogs and humans all may play a role in explaining the discrepancies noted in CSF lactate concentration between dogs and human patients.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study showed a modest increase in mean CSF lactate concentration (3.8 mmol/L from a baseline of 3.1 mmol/L) when sampled immediately after 8 chemically induced seizures in anesthetized dogs ventilated with 100% oxygen 33. A study of experimentally induced seizures in rats showed that CSF lactate concentration was increased as early as 10 minutes after administration of a proconvulsant compound, but had returned to normal by 6 hours after seizures 41. The reason for a lack of increased CSF lactate concentration in the dogs without structural epilepsy in our study is unclear.Discrepancies in experimental methods, species evaluated, anesthetic protocols, arterial oxygen saturation, methods of seizure induction, duration of seizure activity, and number of seizures make comparison among experimental studies challenging.…”

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confidence: 98%

Cerebrospinal fluid lactate concentrations in dogs with seizure disorders

Mariani

Nye

Ruterbories

et al. 2020

Veterinary Internal Medicne

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Background: Cerebrospinal fluid (CSF) lactate concentrations increase after seizure activity in many human patients independent of the underlying disease process. The effect of seizure activity on CSF lactate concentration in dogs is unknown. Hypothesis/Objectives: Cerebrospinal fluid lactate concentration is unaffected by seizure activity in dogs and is more dependent on the underlying disease process causing the seizures. Animals: One-hundred eighteen client-owned dogs with seizure disorders. Methods: Case series. Cerebrospinal fluid lactate concentration was determined using a commercially available lactate monitor. Seizure semiology, time from last seizure to CSF collection, number of seizures within the 72 hours preceding CSF collection, and clinical diagnosis were recorded. Results: Dogs with focal seizures had higher CSF lactate concentrations than did those with generalized seizures (P = .03). No differences in lactate concentrations were found among dogs with single seizures, cluster seizures or status epilepticus (P = .12), among dogs with CSF collection at different time points after the last seizure activity (P = .39) or among dogs having different numbers of seizures within the 72 hours preceding CSF collection (P = .42). A significant difference (P = .001) was found in CSF lactate concentrations among diagnostic groups, and dogs with inflammatory and neoplastic disease had higher concentrations than did dogs with idiopathic or unknown epilepsy.

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“…Lactate levels remained higher than controls for up to 72 h and, histologically, astrocyte damage occurred earlier and more severely than neuronal damage. In another study, induced tonicclonic seizure in rats (Oses et al, 2019) was associated with increased glucose and lactate levels immediately within the brain, with the CSF lactate/glucose ratio remaining >2:1 for 24 h except at the 10 min mark, where it was 1:1. However, mitochondria were not able to increase energy production due to an uncoupling between mitochondrial oxygen consumption and ATP synthesis via FoF1-ATP synthase, thereby affecting cell viability.…”

Section: Diverse Neurology But a Common Factor-perturbed Lactatementioning

confidence: 94%

A Novel, Multi-Faceted Perception of Lactate in Neurology

Mason

2020

Front. Neurosci.

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Sustained elevation of cerebrospinal fluid glucose and lactate after a single seizure does not parallel with mitochondria energy production

Cited by 13 publications

References 49 publications

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Lactate reduces epileptiform activity through HCA1 and GIRK channel activation in rat subicular neurons in an in vitro model

Cerebrospinal fluid lactate concentrations in dogs with seizure disorders

A Novel, Multi-Faceted Perception of Lactate in Neurology

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