Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus

Abstract

The neuroprotective effects of enhancing neuronal inhibition with a gamma-aminobutyric acid (GABA) uptake inhibitor were studied in gerbil hippocampus following transient ischemia. We used in vivo microdialysis to determine a suitable dosing regimen for tiagabine (NNC328) to elevate extracellular levels of GABA within the hippocampus. In anesthetized (normothermic) gerbils, tiagabine (45 mg/kg, i.p.) selectively elevated extracellular GABA levels 450% in area CA1 of the hippocampus. In gerbils subjected to cerebral ischemia via 5-min bilateral carotid occlusion, extracellular GABA levels increased 13-fold in area CA 1 returning to baseline within 30-45 min. When tiagabine was injected 10 min following onset of reperfusion, GABA levels remained elevated (200-470%) for 90 min. In addition, tiagabine significantly reduced the ischemic-induced elevation of glutamate levels in area CA1 during the postischemic period when GABA levels were elevated. There was no effect of postischemic tiagabine on aspartate or six other amino acids. Using the same dosing regimen, we evaluated the degree of neuroprotection in the hippocampus of gerbils 4 and 21 days after ischemia. Tiagabine decreased body temperature a maximum of 2.7 degrees C beginning 30 min into reperfusion and lasting 90 min. In untreated gerbils sacrificed 4 and 21 days after ischemia, there was severe necrosis (99%) of the pyramidal cell layer in area CA1. Whereas tiagabine significantly protected the CA1 pyramidal cell layer in ischemic gerbils at 4 days (overt necrosis confined to about 17% of area CA1), the protection diminished significantly 21 days postischemia. When normothermia was maintained both during and after ischemia in a separate group of tiagabine-treated animals, approximately 77% of the CA1 pyramidal cell layer was necrotic at 4 days. Based on these findings, we suggest that 1) tiagabine slows the development of hippocampal degeneration following ischemia, and 2) that mild, postischemic hypothermia is responsible, in large part, for the neuroprotective actions of this drug. We conclude that the histological outcome after administration of cerebral neuroprotectants should be assessed following long-term survival.

Tacrolimus (FK506) reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study

“…Sustained neuroprotection for approximately 30 days of recovery has also been obtained with benzodiazepine-related compounds (24) and felbamate (25) in the gerbil, and after mild hypothermia in the rat (26). In contrast, the neuroprotective effect of the GABA reuptake inhibitor tiagabine is evident at 4 days, but not after 21 days of recovery (14). These findings emphasize the importance of considering different post-ischemic survival times when the neuroprotective efficacy of drugs is evaluated under conditions of cerebral ischemia.…”

“…Only a single study has investigated whether the neuroprotective effects of FK506 are sustained for post-ischemic periods longer than the commonly used 4-7-day survival time (7). This is an important aspect of neuroprotection since some treatments may merely delay, rather than prevent ischemia-induced cell loss (14).…”

GABA Transporter Deficiency Causes Tremor, Ataxia, Nervousness, and Increased GABA-Induced Tonic Conductance in Cerebellum

“…However, the higher amplitude of hyperthermic episodes in the mGAT1 KO mouse (Fig. 7) clearly does not phenocopy the acute hypothermic effects of tiagabine in rodents (Inglefield et al, 1995). Interestingly, GABA B activation leads to hypothermia (Schuler et al, 2001), but we found previously that the presynaptic GABA B response is diminished or lost in mGAT1 KO mice (Jensen et al, 2003), which may explain the discrepancy.…”

Coactivation of GABA A and GABA B Receptor Results in Neuroprotection During In Vitro Ischemia

“…27 Tiagabine significantly reduced the ischemic-induced elevation of glutamate levels in CA1 area during the postischemic period and protected the CA1 pyramidal cell layer in a gerbil model of transient ischemia. 28,29 In these in vivo experiments, however, postischemic hypothermia occurred, and it may have played a role in the obtained results. Hypothermia is a well-known protective factor against cell damage.…”