Differential modulation of the glutamate transporters GLT1, GLAST and EAAC1 by docosahexaenoic acid

Berry, C. B.; Hayes, Derek; Murphy, Andrew W.; Wiessner, Michael; Rauen, Thomas; McBean, Gethin J.

doi:10.1016/j.brainres.2005.01.008

Cited by 36 publications

(23 citation statements)

References 37 publications

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“…Lamotrigine exerts its anti-seizure effect in this model through a number of mechanisms, mainly inhibition of glutamate and aspartate release by blockade of voltage-dependent Na + channels (Macdonald and Kelly 1995;Armijo et al 2005;White 1999). On the other hand, DHA is also capable of inhibiting glutamatergic transmission (Berry et al 2005). Therefore, it is likely that these mechanisms be involved in the synergistic interaction between DHA and lamotrigine.…”

Section: Probit Of Responsementioning

confidence: 98%

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Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models

Gavzan

Sayyah

Sardari

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Add-on therapy is a common strategy to improve efficacy and tolerability of antiepileptic drugs (AEDs). Anticonvulsant potential and appropriate safety of docosahexaenoic acid (DHA) makes it a promising candidate for combination therapy. We evaluated influence of DHA on anticonvulsant activity of AEDs phenytoin, valproate, and lamotrigine in maximal electroshock (MES), pentylenetetrazole (PTZ), and kindling models of epilepsy. The dose-response to DHA was obtained 15 min after intracerebroventricular (i.c.v.) injection in PTZ model of clonic seizures in mice, MES model of tonic seizures in mice, and kindling model of complex partial seizures in rats. The dose-response curve of valproate (30 min after i.p. injection to mice) in PTZ, phenytoin (60 min after i.p. injection to mice) in MES, and lamotrigine (60 min after i.p. injection to rats) in kindling models were obtained. Dose-response curves of the AEDs were then achieved in the presence of ED25 of DHA. DHA had no anticonvulsant effect in the MES model. However, it showed a dose-dependent protective effect against PTZ (ED50 = 0.13 μM) and kindled seizures (ED50 = 1.08 mM). DHA at ED25 caused a 3.6-fold increase in potency of valproate as its ED50 value from 117.5 (98.3-135.3) decreased to 32.5 (21.6-44.1) mg/kg. Moreover, a 4.9-fold increase in potency of lamotrigine occurred, as its ED50 value from 13.10 (11.50-14.9) decreased to 2.65 (0.8-5.6) mg/kg. CompuSyn analysis indicated synergistic anticonvulsant interaction between DHA and both valproate and lamotrigine. Co-administration strategy of the safe and inexpensive anticonvulsant compound DHA with AEDs should be favorably regarded in clinical studies of epilepsy treatment.

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Section: Probit Of Responsementioning

confidence: 98%

“…Modulation of the neurotransmitter systems is also proposed as a mechanism of DHA antiseizure effects. DHA also increases the uptake of aspartate by excitatory amino acid transporters (Berry et al 2005).…”

Section: Probit Of Responsementioning

confidence: 99%

Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models

Gavzan

Sayyah

Sardari

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Thus, NPD1 or DHA may control the spread of seizures through a mechanism more closely related with epileptogenesis [3] than ictiogenesis [38]. Glutamate transporter 1 (GLT1), glutamate aspartate transporter (GLAST), and excitatory amino acid transporter 1 (EAAC1) are modulated by DHA [39], suggesting that this fatty acid regulates glutamate availability at the synapses through glutamate transporters. Impaired glutamate uptake occurs in experimental models of epilepsy and epileptic patients; as a consequence, glutamate is elevated during induction and propagation of seizures [40].…”

Section: Dha-npd1 Significance In Epileptogenesismentioning

confidence: 99%

Endogenous Signaling by Omega-3 Docosahexaenoic Acid-derived Mediators Sustains Homeostatic Synaptic and Circuitry Integrity

2011

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The harmony and function of the complex brain circuits and synapses are sustained mainly by excitatory and inhibitory neurotransmission, neurotrophins, gene regulation, and factors, many of which are incompletely understood. A common feature of brain circuit components, such as dendrites, synaptic membranes, and other membranes of the nervous system, is that they are richly endowed in docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family. DHA is avidly retained and concentrated in the nervous system and known to play a role in neuroprotection, memory, and vision. Only recently has it become apparent why the surprisingly rapid increases in free (unesterified) DHA pool size take place at the onset of seizures or brain injury. This phenomenon began to be clarified by the discovery of neuroprotectin D1 (NPD1), the first-uncovered bioactive docosanoid formed from free DHA through 15-lipoxygenase-1 (15-LOX-1). NPD1 synthesis includes, as agonists, oxidative stress and neurotrophins. The evolving concept is that DHA-derived docosanoids set in motion endogenous signaling to sustain homeostatic synaptic and circuit integrity. NPD1 is anti-inflammatory, displays inflammatory resolving activities, and induces cell survival, which is in contrast to the pro-inflammatory actions of the many of omega-6 fatty acid family members. We highlight here studies relevant to the ability of DHA to sustain neuronal function and protect synapses and circuits in the context of DHA signalolipidomics. DHA signalolipidomics comprises the integration of the cellular/tissue mechanism of DHA uptake, its distribution among cellular compartments, the organization and function of membrane domains containing DHA phospholipids, and the precise cellular and molecular events revealed by the uncovering of signaling pathways regulated by docosanoids endowed with prohomeostatic and cell survival bioactivity. Therefore, this approach offers emerging targets for prevention, pharmaceutical intervention, and clinical translation involving DHA-mediated signaling.

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“…Indeed, similar antagonistic regulatory mechanisms by different signal transduction pathways have been reported previously. Polyunsaturated fatty acids such as arachidonic acid or docosahexaenoic acid exert the opposite effect on glutamate transporter subtypes inhibiting GLAST and potentiating GLT-1 (Berry et al, 2005;Zerangue et al, 1995). The synthetic glucocorticoid dexamethasone provoked a marked increase in GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected (Zschocke et al, 2005).…”

Section: Discussionmentioning

confidence: 94%

Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3β

Jiménez¹,

Núñez²,

Ibáñez³

et al. 2014

Neurochemistry International

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Differential modulation of the glutamate transporters GLT1, GLAST and EAAC1 by docosahexaenoic acid

Cited by 36 publications

References 37 publications

Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models

Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models

Endogenous Signaling by Omega-3 Docosahexaenoic Acid-derived Mediators Sustains Homeostatic Synaptic and Circuitry Integrity

Differential regulation of the glutamate transporters GLT-1 and GLAST by GSK3β

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