Protective Effect of Gabapentin on N-Methyl-D-aspartate–Induced Excitotoxicity in Rat Hippocampal CA1 Neurons

Kim, Young Sick; Chang, Hyun; Lee, Jin Woo; Sung, Yun Hee; Kim, Sung Eun; Shin, Minsoo; Yi, Jae Woo; Park, Je Hoon; Kim, Hong; Kim, Sang Hoon

doi:10.1254/jphs.08067sc

Cited by 37 publications

(30 citation statements)

References 15 publications

(17 reference statements)

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“…Its mechanism of action is through binding to calcium channels and modulating the influx of calcium and thereby bestowing antiepileptic and analgesic effects. It is not clear if the anti-inflammatory effect of gabapentin is related to calcium modulation rather than other mechanisms such as stimulation of endogenous anti-oxidants like GSH, inhibition of NF-kB, block of NMDA receptor or activation of adenosine A1 receptor (Abdel-Salam and Sleem, 2009; Kim et al, 2009; Yang et al, 2012; Dias et al, 2014; Wang et al, 2014; Martins et al, 2015; Xu et al, 2017). Phosphorylation and calcium concentrations are the effectors modulating the activity of cPLA 2 and recent studies have highlighted the role of PLAs 2 as potential therapeutic target in inflammation and in other serious disorders, and the increase of PLA 2 has been linked with the severity of the disease (Yarla et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

et al. 2017

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To investigate the effects of gabapentin, a structural analog of γ-amino butyric acid (GABA), on the inflammatory response of lipopolysaccharide (LPS)-stimulated rabbit corneal cells (SIRC) and on endotoxin-induced uveitis (EIU) in rabbits. We investigated the LPS-induced expression of several inflammatory mediators, such as TNF-α, IL-1β, cPLA2, COX-2, and PGE2 in the SIRC cells with or without gabapentin treatment. Gabapentin treatment significantly (p < 0.05) attenuated cytokines production, cPLA2 activation, COX-2 expression, and PGE2 levels in SIRC. EIU was induced by an intraocular injection of 0.1 μg of LPS in albino rabbit eye. After 7 and 24 h from LPS injection clinical signs of ocular inflammation were examined by slit lamp with or without topical treatment of 0.5% gabapentin. Tears, aqueous, cornea, conjunctiva, and iris-ciliary body were collected and inflammatory biomarkers assessed. Topical treatment with gabapentin significantly (p < 0.05) reduced clinical signs and biomarkers of inflammation compared with the LPS group both at 7 and 24 h. In conclusion, the results generated in the present study suggest that ophthalmic formulation based on gabapentin may be useful in the treatment of inflammatory conditions associated to ocular pain such as uveitis, and that clinical studies to evaluate this possibility may be warranted.

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Section: Discussionmentioning

confidence: 99%

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

et al. 2017

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“…While our results are consistent with this hypothesis, they do not rule out that GBP has other non-specific effects. GBP has been shown to have effects on calcium currents via its actions on α2δ-1 trafficking (Hendrich et al, 2008; Hoppa et al, 2012) and to have α2δ-1 independent actions on ion channels (Liu et al, 2006) and ligand-gated NMDA and GABA B receptors (Kim et al, 2009; Ng et al, 2001; Lanneau et al, 2001). These effects may play a role in the protective properties of GBP in the FL model.…”

Section: Discussionmentioning

confidence: 99%

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Lau

Hampton

Taylor-Weiner

et al. 2014

Neurobiology of Disease

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Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/ α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/ α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations.

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“…Gabapentin is anchored with α2δ-1 subunits of voltage-gated calcium channel in the dorsal root ganglion, and effectively blocks the influx of Ca 2+ . This binding reduces the secretion of glutamate, aspartate, and P substance, which leads to the inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors, and disrupts nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), which is involved in the generation of cytokines [7,8,17,18,19]. In the central nervous system, gabapentin reduces the presynaptic secretion of gamma-amino butyric acid, while increasing the secretion of glutamate and noradrenaline.…”

Section: Discussionmentioning

confidence: 99%

Analgesic Effect of Intrathecal Gabapentin in a Rat Model of Persistent Muscle Pain

et al. 2014

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ObjectiveTo evaluate the analgesic effect of intrathecal gabapentin therapy on secondary hyperalgesia in a rat model of persistent muscle pain.MethodsIntrathecal catheters were implanted into rats. Mechanical secondary hyperalgesia was induced by repeated intramuscular injections of acidic solution into the gastrocnemius muscle. Gabapentin was administrated intrathecally. Rats were allocated to control and experimental (gabapentin 30, 100, 300, and 1,000 µg) group. After gabapentin administration, mechanical withdrawal threshold was measured every 15 minutes and the motor function was measured 30 minutes later.ResultsMechanical hyperalgesia was evoked after the second acidic buffer injection. There was a significant improvement on the mechanical threshold after administration of 100, 300, and 1,000 µg gabapentin compared to pre-injection and the control group. The analgesic effect continued for 105, 135, and 210 minutes, respectively. To discern side effects, motor function was measured. Motor function was preserved in both groups after gabapentin administration, except for rats who received 1,000 µg gabapentin.ConclusionIntrathecal gabapentin administration produces dose-dependent improvements in mechanical hyperalgesia in a persistent muscle pain rat model. This implicates the central nervous system as having a strong influence on the development of persistent mechanical hyperalgesia. These results are helpful in understanding the pathophysiology of secondary hyperalgesia and in the treatment of patients with chronic muscle pain.

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Protective Effect of Gabapentin on N-Methyl-D-aspartate–Induced Excitotoxicity in Rat Hippocampal CA1 Neurons

Cited by 37 publications

References 15 publications

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation

Analgesic Effect of Intrathecal Gabapentin in a Rat Model of Persistent Muscle Pain

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