The effects of gabapentin pretreatment on brain injury induced by focal cerebral ischemia/reperfusion in the rat

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Abstract

Background

Experimental studies have shown that gabapentin can reduce neuronal injury in the setting of cerebral ischemia, but the mechanisms have not yet been clearly determined. This study was conducted to determine whether gabapentin pretreatment altered expression levels of heat shock protein 70 and reduced acute phase neuronal injury in rats subjected to transient focal cerebral ischemia/reperfusion.

Methods

Forty male Sprague-Dawley rats (260-300 g) were randomly assigned to one of four groups (saline-treated, or 0.1, 0.5, or 5 mg/kg gabapentin group). In all animals, focal cerebral ischemia was induced by intraluminal middle cerebral artery occlusion for 1 hour. The animals of the gabapentin groups were pretreated with a single intravenous administration of gabapentin 20 minutes before ischemic insults. The infarct volume, brain edema and motor behavior deficits were analyzed 24 hours after ischemic insult. Caspase-3-reactive cells and cells showing Hsp70 activity were counted in the caudoputamen and fronto-parietal cortex.

Results

The infarction ratio was significantly decreased in the 5 mg/kg gabapentin group (P < 0.05) and brain edema ratios were significantly reduced in the 0.1 mg/kg, 0.5 mg/kg, and 5 mg/kg gabapentin groups 24 hours after ischemia/reperfusion injury (P < 0.05). There were more Hsp70-reactive cells in the 5 mg/kg gabapentin group than in the saline group in both the caudoputamen and fronto-parietal cortex (P < 0.05).

Conclusions

These results indicate that gabapentin may have a neuroprotective effect and can reduce early neuronal injury caused by focal cerebral ischemia/reperfusion; this may be mediated by expression of Hsp70. However, gabapentin pretreatment did not prevent caspase-dependent apoptosis.

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Most cited references 21

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The mechanisms of action of gabapentin and pregabalin.

Graeme J. Sills (2006)

Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear. The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the alpha2delta-1 subunit. This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.

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Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.

P Harden, L. Miller, M Rowbotham … (1998)

Postherpetic neuralgia (PHN) is a syndrome of often intractable neuropathic pain following herpes zoster (shingles) that eludes effective treatment in many patients. To determine the efficacy and safety of the anticonvulsant drug gabapentin in reducing PHN pain. Multicenter, randomized, double-blind, placebo-controlled, parallel design, 8-week trial conducted from August 1996 through July 1997. Sixteen US outpatient clinical centers. A total of 229 subjects were randomized. A 4-week titration period to a maximum dosage of 3600 mg/d of gabapentin or matching placebo. Treatment was maintained for another 4 weeks at the maximum tolerated dose. Concomitant tricyclic antidepressants and/or narcotics were continued if therapy was stabilized prior to study entry and remained constant throughout the study. The primary efficacy measure was change in the average daily pain score based on an 11-point Likert scale (0, no pain; 10, worst possible pain) from baseline week to the final week of therapy. Secondary measures included average daily sleep scores, Short-Form McGill Pain Questionnaire (SF-MPQ), Subject Global Impression of Change and investigator-rated Clinical Global Impression of Change, Short Form-36 (SF-36) Quality of Life Questionnaire, and Profile of Mood States (POMS). Safety measures included the frequency and severity of adverse events. One hundred thirteen patients received gabapentin, and 89 (78.8%) completed the study; 116 received placebo, and 95 (81.9%) completed the study. By intent-to-treat analysis, subjects receiving gabapentin had a statistically significant reduction in average daily pain score from 6.3 to 4.2 points compared with a change from 6.5 to 6.0 points in subjects randomized to receive placebo (P<.001). Secondary measures of pain as well as changes in pain and sleep interference showed improvement with gabapentin (P<.001). Many measures within the SF-36 and POMS also significantly favored gabapentin (P< or =.01). Somnolence, dizziness, ataxia, peripheral edema, and infection were all more frequent in the gabapentin group, but withdrawals were comparable in the 2 groups (15 [13.3%] in the gabapentin group vs 11 [9.5%] in the placebo group). Gabapentin is effective in the treatment of pain and sleep interference associated with PHN. Mood and quality of life also improve with gabapentin therapy.

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Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.

Linda M. Field, Tim McCleary, L Singh … (1997)

1. Gabapentin (neurontin) is a novel antiepileptic agent that binds to the alpha 2 delta subunit of voltage-dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)-(+)-enantiomer of 3-isobutylgaba. However, the corresponding (R)-(-)-enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3-isobutylgaba in formalin and carrageenan-induced inflammatory pain models. 2. In the rat formalin test, S-(+)-3-isobutylgaba (1-100 mg kg-1) and gabapentin (10-300 mg kg-1) dose-dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg-1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1-10.0 mg kg-1, s.c.). In contrast, the R-(-)-enantiomer of 3-isobutylgaba (1-100 mg kg-1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg-1. However, none of the compounds showed any effect during the early phase of the response. 3. The s.c. administration of either S-(+)-3-isobutylgaba (1-30 mg kg-1) or gabapentin (10-100 mg kg-1), after the development of peak carrageenan-induced thermal hyperalgesia, dose-dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg-1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan-induced mechanical hyperalgesia with MED of 3 and 10 mg kg-1, respectively. In contrast, R-(-)-3-isobutylgaba failed to show any effect in the two hyperalgesia models. 4. The intrathecal administration of gabapentin dose-dependently (1-100 micrograms/animal) blocked carrageenan-induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response. 5. Unlike morphine, the repeated administration of gabapentin (100 mg kg-1 at start and culminating to 400 mg kg-1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10-300 mg kg-1), R-(-) (3-100 mg kg-1) or S-(+)-3-isobutylgaba (3-100 mg kg-1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1-100 mg kg-1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30-300 mg kg-1) and S-(+)-isobutylgaba (1-100 mg kg-1) showed sedative/ataxic properties only at the highest dose tested in the rota-rod apparatus. 6. Gabapentin (30-300 mg kg-1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

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Author and article information

Journal

Journal ID (nlm-ta): Korean J Anesthesiol

Journal ID (publisher-id): KJAE

Title: Korean Journal of Anesthesiology

Publisher: The Korean Society of Anesthesiologists

ISSN (Print): 2005-6419

ISSN (Electronic): 2005-7563

Publication date (Print): February 2010

Publication date (Electronic): 28 February 2010

Volume: 58

Issue: 2

Pages: 184-190

Affiliations

Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Author notes

Corresponding author: Jeong Gill Leem, M.D., Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap-dong, Songpa-gu, Seoul 138-040, Korea. Tel: 82-2-3010-3861, Fax: 82-2-470-1363, jgleem@ 123456amc.seoul.kr

Article

DOI: 10.4097/kjae.2010.58.2.184

PMC ID: 2872851

PubMed ID: 20498798

SO-VID: a5d560d6-9ba0-49a1-8c0d-1a648d73f219

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The effects of gabapentin pretreatment on brain injury induced by focal cerebral ischemia/reperfusion in the rat

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Abstract

Background

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Conclusions

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Irish Journal of Paramedicine

Most cited references 21

The mechanisms of action of gabapentin and pregabalin.

Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial.

Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents.

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