Efficacy of a New Neuroprotective Agent, Gacyclidine, in a Model of Rat Spinal Cord Injury

Feldblum, Sophie; Arnaud, Sonia; Simon, Marilyn K.; Rabin, Olivier; D’Arbigny, Pierre

doi:10.1089/neu.2000.17.1079

Cited by 37 publications

(24 citation statements)

References 25 publications

(30 reference statements)

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“…69 In SCI models, administration of an NMDA antagonist, gacyclidine, leads to improved motor function recovery, and reduced astrogliosis. 70 Similarily, administration of a different antagonist, MK-801, produces dose dependent reduction in thermal hyperalgesia but slower analgesic effects. 71 Another NMDA antagonist, CHF3381, showed reduced hyperalgesia in improving pain in humans.…”

Section: Introductionmentioning

confidence: 98%

Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms

Schomberg¹,

Ahmed²,

Miranpuri³

et al. 2012

ANS

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Neuropathic pain (NP) is a significant and disabling clinical problem with very few therapeutic treatment options available. A major priority is to identify the molecular mechanisms responsible for NP. Although many seemingly relevant pathways have been identified, more research is needed before effective clinical interventions can be produced. Initial insults to the nervous system, such as spinal cord injury (SCI), are often compounded by secondary mechanisms such as inflammation, the immune response, and the changing expression of receptors and ion channels. The consequences of these secondary effects myriad and compound those elicited by the primary injury. Chronic NP syndromes following SCI can greatly complicate the clinical treatment of the primary injury and result in high comorbidity. In this review, we will describe physiological outcomes associated with SCI along with some of the mechanisms known to contribute to chronic NP development.

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Section: Introductionmentioning

confidence: 98%

Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms

Schomberg¹,

Ahmed²,

Miranpuri³

et al. 2012

ANS

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“…Glutamate excitotoxicity due to overstimulation of glutamate receptors, in particular NMDA receptors, is believed to play a key role in the initiation of neuronal cell death following SCI (for a review, see Park et al 20 ); thus development of pharmacological approaches has largely been directed toward the prevention of glutamate-induced excitotoxicity. In particular gacyclidine (GK11), a noncompetitive-NMDA receptor antagonist has been shown to be effective after experimental ischemic and contusive SCI 4,7,8 and has already been used in a clinical trial. 25 In order for the model to be thoroughly characterized, which is a prerequisite for its use as a preclinical test, it is necessary to perform a complete functional survey, including detailed time course, quantitative anatomical control, and pharmacological evaluation.…”

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confidence: 99%

Early functional outcomes and histological analysis after spinal cord compression injury in rats

Lonjon

Kouyoumdjïan

Prieto³

et al. 2010

SPI

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Object Neuroprotective and repair strategies in spinal cord injuries (SCIs) have been so far largely unsuccessful. One of the prerequisites is the use of appropriate preclinical models to decipher pathophysiological mechanisms; another is the identification of optimal time windows for therapeutic interventions. The authors undertook this study to characterize early motor, sensory, autonomic, and histological outcomes after balloon compression of the spinal cord at the T8–9 level in adult rats. Methods A total of 91 rats were used in this study. Spinal cord balloon compression was performed at T8–9 in adult rats by inflation of a 2 Fr Fogarty catheter into the epidural space. The authors first characterized early motor, sensory, and autonomic outcomes of 2 volumes of compression (10 and 15 μl) using behavioral tests and then examined histological outcomes in the spinal cord using Luxol fast blue staining. To further substantiate the characterization of the epidural balloon-compression model, they used a noncompetitive N-methyl-d-aspartate antagonist, GK11, and demonstrated the involvement of excitotoxicity in this model. Results Proportional and reproducible functional impairment resulted from compression caused by balloon inflation with either 10 or 15 μl of water and corresponded to the extent of the lesion. Indeed, during the early phase following SCI (1 week postinjury), recovery of locomotor function and bladder control correlated with the volume of inflation, whereas outcomes with respect to sensory function and reflexes were independent of compression severity. Treatment with GK11 significantly improved motor function in all groups of rats 1 week after injury and bladder voiding in the 10-μl injured rats compared to the 15-μl injured rats. Conclusions The results of this study demonstrate that spinal balloon-compression injury in the rat is a well-characterized, reproducible, and predictable model to analyze early events following SCI.

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“…Astrogliosis is a prominent reaction to traumatic spinal cord injury (36)(37)(38)(39)(40). After injury, inflammatory responses rapidly induce marked astrocytic changes, referred to as reactive gliosis.…”

Section: Discussionmentioning

confidence: 99%

Ait-082 and Methylprednisolone Singly, but Not in Combination, Enhance Functional and Histological Improvement after Acute Spinal Cord Injury in Rats

Jiang

Khan²,

Pj³

et al. 2004

Int J Immunopathol Pharmacol

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Extracellular non-adenine based purines are neuroprotective. Preliminary studies indicate that administration of the synthetic purine 4–[[3–(1,6 dihydro-6-oxo-9- purine-9-yl)-1-oxypropyl] amino] benzoic acid (AIT-082, leteprinim potassium) to rats immediately after acute spinal cord injury (SCI), improves functional outcome. The effects of potential new agents are often compared to methylprednisolone (MPSS). We evaluated the effects of AIT-082 and MPSS, separately and in combination, on the functional and morphological outcome of acute SCI in adult rats. After standardized T11–12 spinal cord compression rats were given intraperitoneally one of the following: vehicle (saline); MPSS (30 mg/kg or 60 mg/kg body weight, first dose 15 min after crush); AIT-082 (60 mg/kg body weight daily, first dose 15 min after crush); or AIT-082 plus MPSS. After 1, 3, or 21 days, the rats were perfused for histological analysis. AIT-082 administrations significantly reduced locomotor impairment from 1–21 days post-operatively. At 1 and 3 days post injury, AIT-082-treatment reduced tissue swelling, tissue loss and astrogliosis at the injured cords but did not alter the extent of hemorrhage and the number of macrophages and/or microglia. MPSS reduced hemorrhage and the number of macrophages and/or microglia, but did not alter astrogliosis. At 21 days, either AIT-082 or MPSS administration improved function and morphology similarly (less tissue loss and astrogliosis). In contrast, administration of AIT-082 and MPSS together abolished the beneficial effects observed when either drug was given individually. These results suggest that MPSS and AIT-082 may exert their beneficial effects through different and potentially antagonistic pathways.

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Efficacy of a New Neuroprotective Agent, Gacyclidine, in a Model of Rat Spinal Cord Injury

Cited by 37 publications

References 25 publications

Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms

Neuropathic pain: role of inflammation, immune response, and ion channel activity in central injury mechanisms

Early functional outcomes and histological analysis after spinal cord compression injury in rats

Ait-082 and Methylprednisolone Singly, but Not in Combination, Enhance Functional and Histological Improvement after Acute Spinal Cord Injury in Rats

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