Neuronal Death In Gerbils Research Articles

Wide therapeutic time window for fasudil neuroprotection against ischemia-induced delayed neuronal death in gerbils

The neuroprotective potential and therapeutic time window for fasudil, a Rho-kinase inhibitor (RKI), were evaluated for delayed neuronal death in gerbils. A preliminary screening was done on fasudil, ozagrel, and edaravone using a single administration in a delayed neuronal death study. Intraperitoneal (i.p.) administration of edaravone, a free radical scavenger (3, 10 mg/kg) immediately after re-circulation did not reduce neuronal degeneration. We previously reported that ozagrel, a thromboxane A 2 synthetase inhibitor (30 mg/kg) also did not reduce neuronal degeneration, while fasudil (3, 30 mg/kg) significantly protected against the ischemia-induced neuronal loss. To clarify the therapeutic time window of fasudil, which showed a positive effect in a preliminary screening, animals received their first i.p. administration of fasudil (10 mg/kg) 24 or 48 h after ischemia. Administration of fasudil twice daily was continued until day 6. Fasudil significantly protected against the ischemia-induced delayed neuronal death when the treatment was started 24 h after ischemia. In gerbils, hydroxyfasudil, an active metabolite of fasudil, was found following an i.p. administration of fasudil (10 mg/kg), and the value of the area under the plasma level curve of hydroxyfasudil was 7 times higher than that of fasudil. Hydroxyfasudil may contribute to the potency of fasudil. The present findings indicate that the RKI fasudil reduces ischemic neuronal damage with a wide therapeutic time window in gerbil, and may be useful in the treatment of acute ischemic stroke in humans.

Dietary grape supplement ameliorates cerebral ischemia-induced neuronal death in gerbils

Oxidative damage has been implicated as one of the leading causes for neuronal cell death in a number of neurodegenerative diseases including stroke. Many vegetables and fruits are enriched in polyphenolic compounds known to exhibit antioxidant properties. This study is to investigate whether dietary supplement with grape powder (GP) may offer protection against neuronal damage due to global cerebral ischemia induced to Mongolian gerbils by occlusion of the common carotid arteries, a model known to cause delayed neuronal death (DND) in the hippocampal CA1 area. Gerbils were fed either a control diet (AIN76a) or a control diet supplemented with low (5.0 g/kg diet) or high (50 g/kg diet) levels of GP for two months. Four days after ischemia/reperfusion (I/R), the extent of DND, glial cell activation, nuclear DNA oxidation, and apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) reaction in hippocampal CA1 region were assessed. Ischemia-induced extensive DND in the CA1 region was accompanied by oxidative and fragmented DNA damage and a marked increase in reactive astrocytes and microglial cells. Dietary GP supplementation significantly protected neurons against I/R-induced DND, DNA damage, and apoptosis as well as attenuated glial cell activation. These results demonstrate that due to the antioxidant properties of polyphenols in GP, nutritional diets supplemented with grape can protect the brain against ischemic damage. The neuroprotective effects of GP supplement may have wide implication in the future for prevention/protection against other neurodegenerative damage.

Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils.

Sendai virus (SeV) vector-mediated gene delivery of glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) prevented the delayed neuronal death induced by transient global ischemia in gerbils, even when the vector was administered several hours after ischemia. Intraventricular administration of SeV vector directed high-level expression of the vector-encoded neurotrophic factor genes, which are potent candidates for the treatment of neurodegenerative diseases. After occlusion of the bilateral carotid arteries of gerbils, SeV vector carrying GDNF (SeV/GDNF), NGF (SeV/NGF), brain-derived neurotrophic factor (SeV/BDNF), insulin-like growth factor-1 (SeV/IGF-1) or vascular endothelial growth factor (SeV/VEGF) was injected into the lateral ventricle. Administration of SeV/GDNF, SeV/NGF or SeV/BDNF 30 min after the ischemic insult effectively prevented the delayed neuronal death of the hippocampal CA1 pyramidal neurons. Furthermore, the administration of SeV/GDNF or SeV/NGF as late as 4 or 6 h after the ischemic insult also prevented the death of these neurons. These results indicate that SeV vector-mediated gene transfer of neurotrophic factors has high therapeutic potency for preventing the delayed neuronal death induced by transient global ischemia, and provides an approach for gene therapy of stroke.

Proliferation of Leptomeningeal Cells in Delayed Neuronal Death in Gerbils

Glial and vascular cell proliferation is known to be induced in several neurological disorders of the central nervous system. However, whether leptomeningeal cells proliferate in response to neuronal disorders including brain infarction or hemorrhage, remains unknown. We assessed 3H-thymidine incorporation into proliferating leptomeningeal cells in delayed neuronal death following a transient forebrain ischemia for 5 min in gerbils; the CA1 hippocampal neurons died 2-6 days after the ischemia. The number of 3H-labeled leptomeningeal cells started to increase 2 days after ischemia and reached 5 times that of the sham-operated animals 6 days after ischemia. The proliferative response was suppressed to the baseline level at 8 days after ischemia. The total number of leptomeningeal cells (3H-labeled and unlabeled cells) also started to increase 2 days after ischemia and reached 1.4 times at 4-8 days after that. These observations indicated that leptomeningeal cells begin to proliferate in response to ischemia-induced neuronal death in the central nervous system.

Five percent, 7.5% or 10% hypertonic saline prevents delayed neuronal death in gerbils.

To clarify the appropriate concentration and dose of hypertonic saline solution (HSS) for preventing delayed neuronal death in the hippocampal CA1 subfield after transient forebrain ischemia in gerbils. Thirty gerbils were randomly assigned to five groups: physiological saline solution (PSS) group, ischemia/reperfusion treated with PSS 2 mL x kg(-1); 5% HSS group, treated with 5% HSS 2 mL x kg(-1); 7.5% HSS group, treated with 7.5% HSS 2 mL x kg(-1); 10% HSS group, treated with 10% HSS 2 mL x kg(-1); 20% HSS group, treated with 20% HSS 2 mL x kg(-1). Transient forebrain ischemia was induced by occluding the bilateral common carotid arteries for four minutes. Five days later, histopathological changes in the hippocampal area were examined, and the degenerative ratio of the pyramidal cells were measured according to the following formula: (number of degenerative pyramidal cells/total number of pyramidal cells per 1 mm of hippocampal CA1 subfield) x 100. In PSS and 20% groups, neuronal cell damage was observed five days after ischemia. In the other three groups, these changes were not observed. The degenerative ratios of pyramidal cells were as follows; PSS group: 91.6 +/- 5.6%, 5% HSS group: 7.2 +/- 1.6%, 7.5% group: 8.3 +/- 1.4%, 10% HSS group: 6.2 +/- 1.1%, 20% HSS group: 85.8 +/- 8.7% (P < 0.05; PSS and 20% HSS vs three other groups). This study demonstrates that 5, 7.5 or 10% HSS 2 mL x kg(-1) may prevent delayed neuronal death in the hippocampal CA1 subfield after cerebral ischemia/reperfusion in gerbils.

758. Several Hours Post-Ischemic Administration of Sendai Virus Vectors Carrying Neurotrophic Factor Genes Prevent the Delayed Neuronal Death in Gerbils

758. Several Hours Post-Ischemic Administration of Sendai Virus Vectors Carrying Neurotrophic Factor Genes Prevent the Delayed Neuronal Death in Gerbils

Pharmacological profile of hydroxy fasudil as a selective rho kinase inhibitor on ischemic brain damage

The neuroprotective property and the effects on hemodynamics of hydroxy fasudil, an active metabolite of an antispastic drug, fasudil, were examined. In rats, hydroxy fasudil was found following intravenous infusion or intraperitoneal administration of fasudil, and the maximum plasma concentration of hydroxy fasudil was approximately 25 or 40% of the parent drug, respectively. The i.v. administration of hydroxy fasudil produced significant increases in regional cerebral blood flow in dogs. Hydroxy fasudil relaxed the KCl, PGF 2 α or U-46619-induced contraction in canine basilar or middle cerebral arterial strips, concentration-dependently. The neuroprotective property of hydroxy fasudil was examined on delayed neuronal death in gerbils. Hydroxy fasudil (3 mg/kg) significantly protected against the ischemia-induced neuronal loss. To further clarify the effect on neurological impairments, hydroxy fasudil was tested in a rat model of microembolization stroke. Intravenous administration of hydroxy fasudil improved neurological functions, significantly reduced the size of the infarct area and prevented the accumulation of neutrophils. The present findings suggest that hydroxy fasudil has an efficacy to improve the hemodynamic function and to inhibit neutrophil-mediated damage, and contributes to the potency and long duration of the cytoprotective properties of fasudil on ischemic brain damage, and also suggest a critical role for rho kinase in the pathogenesis of cerebral ischemic injury, and the potential utility of rho kinase inhibitor as a therapeutic agent in stroke.

Protective effect of γ-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils

We examined the protective effect of γ-glutamylethylamide (theanine) on ischemic delayed neuronal death in field CA1 of the gerbil hippocampus. One microliter of theanine from each three concentrations (50, 125 and 500 μM) was administered through the lateral ventricle 30 min before ischemia. Transient forebrain ischemia was induced by bilateral occlusion of the common carotid arteries for 3 min under careful control of brain temperature at approximately 37°C. Seven days after ischemia, the number of intact CA1 neurons in the hippocampus was assessed. Ischemia-induced neuronal death in hippocampal CA1 region was significantly prevented in a dose-dependent manner in the theanine-pretreated groups. These findings indicate that theanine might be useful clinically for preventing ischemic neuronal damage.

Indomethacin inhibits delayed DNA fragmentation of hippocampal CA1 pyramidal neurons after transient forebrain ischemia in gerbils

Recent studies have shown a close association between reactive oxygen species and DNA fragmentation and that delayed neuronal death after transient forebrain ischemia manifests as DNA fragmentation-like apoptosis. We examined the effect of indomethacin on ischemic-induced delayed hippocampal neuronal death in gerbils using the TUNEL staining method, since indomethacin is neuroprotective in a variety of degenerative processes, such as Alzheimer's disease. Indomethacin (5 mg/kg, i.p.), administered 5 min before the ischemic insult, significantly decreased the number of TUNEL-positive hippocampal CA1 pyramidal neurons and delayed the appearance of TUNEL-positive neurons. Our results indicate that indomethacin is effective in inhibiting DNA fragmentation after transient forebrain ischemia.

Ginsenoside Rb1 prevents image navigation disability, cortical infarction, and thalamic degeneration in rats with focal cerebral ischemia

Oral administration of red ginseng powder before but not after transient forebrain ischemia prevents delayed neuronal death in gerbils. One neuroprotective molecule within red ginseng powder is ginsenoside Rb(1). The mechanism of action(s) of ginsenoside Rb(1) remains to be determined. We performed intracerebroventricular infusion of 0.6 microg/d ginsenoside Rb(1) before or after permanent occlusion of the left middle cerebral artery in stroke-prone spontaneous hypertensive rats. Ginsenoside Rb(1) significantly decreased escape latency on repeated trials of the Morris water maze test, throughout the first to fourth trial days at 2 and 4 weeks after MCA occlusion (P<.05, P<.01 or P<.001). The ratio of the infarcted area to the left hemispheric area in the groups treated with 0.6 microg/d of ginsenoside Rb(1) was significantly smaller than that in the saline-treated ischemic group (P<.05 or P<.001). The continuous infusion of ginsenoside Rb(1) (0.06 microg/d) was less effective and the other doses examined were ineffective in ameliorating ischemia-induced image navigation disability and reducing cortical infarct size. There were significant differences in neuron numbers in the ventroposterior thalamic nucleus and in the left-to-right ratio of the thalamic area between the saline-infused ischemic group and the ginsenoside Rb(1)-treated ischemic group (P<.05 or P<.01). Moreover, ginsenoside Rb(1) at concentrations of 0.1 to 100 fg/mL (0.09 to 90 fM), facilitated neurite extension and rescued cortical neurons from lethal damage caused by the free radical-promoting agent FeSO(4), in vitro (P<.05 or P<.01). These findings suggest that ginsenoside Rb(1) protects the cerebral cortex against lethal ischemic damage possibly by acting as a neurotrophic factor-like agent and by scavenging free radicals, which are overproduced in situ during and after brain ischemia. The final link between the in vivo neuroprotective action and the in vitro neurotrophic and antioxidant activities of ginsenoside Rb(1) remains to be determined.

Protection of ischemic hippocampal neurons by ginsenoside Rb 1, a main ingredient of ginseng root

Our previous study showed that the oral administration of red ginseng powder before but not after transient forebrain ischemia prevented delayed neuronal death in gerbils, and that a neuroprotective molecule within red ginseng powder was ginsenoside Rb 1. However, it remains to be clarified whether or not ginsenoside Rb 1 acts directly on the ischemic brain, and the mechanism by which ginsenoside Rb 1 protects the ischemic CA1 neurons is not determined. Without elucidation of the pharmacological property of ginsenoside Rb 1, the drug would not be accepted as a neuroprotective agent. The present study demonstrated that the intracerebroventricular infusion of ginsenoside Rb 1 after 3.5 min or 3 min forebrain ischemia, precluded significantly the ischemia-induced shortening of response latency in a step-down passive avoidance task and rescued a significant number of hippocampal CA1 neurons from lethal ischemic damage. The intracerebroventricular infusion of ginsenoside Rb 1 did not affect hippocampal blood flow or hippocampal temperature except that it caused a slight increase in hippocampal blood flow at 5 min after transient forebrain ischemia. Furthermore, ginsenoside Rb 1 at concentrations of 0.1–100 fg/ml (0.09–90 fM) rescued hippocampal neurons from lethal damage caused by the hydroxyl radical-promoting agent FeSO 4 in vitro, and the Fenton reaction system containing p-nitrosodimethylaniline confirmed the hydroxyl radical-scavenging activity of ginsenoside Rb 1. These findings suggest that the central infusion of ginsenoside Rb 1 after forebrain ischemia protects hippocampal CA1 neurons against lethal ischemic damage possibly by scavenging free radicals which are overproduced in situ after brain ischemia and reperfusion. The present study may validate the empirical usage of ginseng root over thousands of years for the prevention of cerebrovascular diseases.

Selegiline treatment after transient global ischemia in gerbils enhances the survival of CA1 pyramidal cells in the hippocampus

Selegiline ( l-deprenyl) has shown neuroprotective effects in a variety of degenerative processes. The present experiments were designed to test whether post-ischemia administered selegiline would alleviate delayed neuronal death of the gerbil hippocampal pyramidal cells following transient global ischemia. Common carotid arteries were occluded for 5 min. Saline or selegiline, 0.25 mg/kg s.c., was administered 2 h after the ischemia followed by a daily injection for either 3 or 7 days. After decapitation, the delayed death of the hippocampal CA1 pyramidal cells was assessed using Nissl-stained sections. In situ hybridization was used to reveal the expression of hsp70 mRNA 1, 3 or 7 days after the ischemia. Animals treated with selegiline for 7 days showed significantly lower damage score (scale 0–3: 0, normal; 1, <10% of the neurons damaged; 2, 10–50% damaged; 3, >50% damaged) compared to the saline-treated animals 1.73±0.18 and 2.41±0.16 (mean±S.E.M., P=0.0133), respectively. A similar trend was found in animals after the 3-day treatment: 1.68±0.32 vs. 2.06±0.25 ( P>0.5). The expression of hsp70 mRNA in the CA1 pyramidal cell layer was strong still 3 days after the ischemic insult but vanished by 7 days. Densitometric measurements using 14C-plastic standards showed that the intensity of the CA1a hsp70 signal on the 3rd day correlated negatively to the cell-damage score ( r=−0.72, P<0.001), suggesting that hsp70 does not serve as a quantitative marker for CA1 neuronal injury in this model. Instead, the hsp70 expression was associated with improved neuronal survival lasting often longer in selegiline-treated animals ( P>0.5). The results show that a low dose of selegiline can alleviate the delayed hippocampal neuronal death in gerbils when administered 2 h after an ischemic insult.

Effect of immunosuppressant FK506 on ischemia-induced degeneration of hippocampal neurons in gerbils

To evaluate the effect of FK506 on delayed neuronal death in gerbils after forebrain ischemia, 84 adult Mongolian gerbils were used in this study. Transient forebrain ischemia was induced by clipping common carotid arteries bilaterally for 5 minutes. One hour after reperfusion, we intraperitoneally injected FK506 (1.0 mg/kg), cyclosporin A (CsA) (10.0 mg/kg) or the vehicle solution into each gerbil. In one group, each agent was additionally administered daily 3 more times at 24, 48 and 72 hours after ischemia. The gerbils were killed 4 days or 10 days after transient ischemia, and damage to their hippocampal pyramidal cells was histologically assessed. Additionally, the body temperature was measured following administration of each drug to investigate drug-induced hypothermia. Post-ischemic repeated treatment with FK506 significantly (p < 0.01) reduced degeneration of hippocampal neurons. However, partial treatment did not modify neuronal degeneration. CsA did not show a neuroprotective effect in this study. Drug-induced mild hypothermia (35–37 C) was observed following administration of FK506 or CsA. There was no significant difference in the time course of the body temperature between the FK506 and CsA group. We demonstrated that the repeated FK506 treatment, but not the CsA treatment, reduced ischemia-induced degeneration of hippocampal neurons in gerbils. Although FK506-induced hypothermia might have modified neuronal degeneration, a comparison with CsA indicated that the neuroprotective effect of FK506 was not solely due to hypothermia per se.

Neuroprotective properties of a protein kinase inhibitor against ischaemia-induced neuronal damage in rats and gerbils.

1. The neuroprotective properties of fasudil (HA1077), a novel protein kinase inhibitor, were evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in Mongolian gerbils and cerebral microembolization in rats. 2. The cytoprotective effect of fasudil on delayed neuronal death in gerbils was compared with the effects of nimodipine, a calcium channel antagonist and ozagrel, a thromboxane A2 synthetase inhibitor. The average of the neuronal cell density in the ischaemic control group was 17.8 +/- 2.1 cells mm-1, whereas fasudil (30 mg kg-1) significantly diminished the loss of CA1 neurones with the average of the neuronal cell density of 101.0 +/- 22.0 cells mm-1; nimodipine (10 mg kg-1) and ozagrel (30 mg kg-1) did not significantly protect against the ischaemia-induced neuronal loss. 3. In the rat model, the effects of fasudil on the histological and neurological consequences of cerebral microembolization produced via the injection of microspheres were examined. Twenty-four hours after the injection of microspheres into the internal carotid artery, all animals in the control group showed typical symptoms of stroke. Neurological function was significantly improved in the fasudil-treated animals. In the controls, the infarcted area in a cortical slice selected to include the hippocampal area was 0.25 +/- 0.01 cm2 (mean +/- s.e.mean) (43.9 +/- 2.4% of cortical section of the half hemisphere); the difference was significant compared to the mean area of 32.7 +/- 2.8 and 21.5 +/- 4.8% observed in rats treated with fasudil (3, 10 mg kg-1), respectively. Fasudil (10 mg kg-1) significantly suppressed the increased water content in ischaemic brain tissues (saline-treated rats, 82.4 +/- 0.2% vs fasudil-treated rats, 81.0 +/- 0.4%). 4. These results suggest that: (i) various protein kinases are involved in the pathogenesis of ischaemic injury; and (ii) the inhibition of protein kinases may be efficacious in preventing neuronal death, thus improving neurological function in the brain damage associated with ischaemic stroke.

Guanidinoethane sulfate is neuroprotective towards delayed CA1 neuronal death in gerbils.

The potential neuroprotective effects of guanidinoethane sulfate (GES) on delayed neuronal death of hippocampal CA1 neurons were investigated using a gerbil model of forebrain ischemia. Neuronal densities of CA1 neurons in the saline control group (255.1 +/- 11.7 cells/mm) and guanidinoethane sulfate pretreated control group (249.0 +/- 9.4 cells/mm) showed no significant differences. By contrast, in animals subjected to ischemia, CA1 neurons of the guanidinoethane sulfate pretreated group showed a significantly higher number of surviving neurons (61.1 +/- 55.11 cells/mm) compared to the saline group (17.75 +/- 12.73 cells/mm) (p < 0.05, t-test). The study indicated that although partial, guanidinoethane sulfate is neuroprotective towards gerbil hippocampal CA1 neurons against ischemic insult.

The protective effect of L-threo-3,4-dihydroxyphenylserine on ischemic hippocampal neuronal death in gerbils.

L-Threo-3,4-dihydroxyphenylserine (DOPS) is reported to increase the nerve growth factor (NGF) synthesis in cultured mouse L-M fibroblast and astroglial cells, and this effect is not blocked by treatment with decarboxylase inhibitor. NGF is suggested to play an important role in neuronal survival and regeneration under pathological conditions. We evaluated the possible protective effect of DOPS against hippocampal CA1 cell death after transient forebrain ischemia in gerbils. Male mongolian gerbils were treated with DOPS (30, 100, or 300 mg/kg IP) plus benserazide (10 mg/kg IP) (n = 28) or vehicle (n = 7) before 3.5 minutes of forebrain ischemia. For histopathologic study, the animals were decapitated 7 days after recirculation, and neuronal density of the hippocampal CA1 area was counted after cresyl violet staining. For immunohistochemical study, another group of gerbils (n = 34) was recovered for 1, 3, and 8 hours and 1, 2, and 7 days, when they were decapitated. The brain sections were stained against NGF, NGF receptor, and HSP70 using the avidin-biotin-peroxidase method. Preservation of the hippocampal CA1 cells was found in the brains treated with 300 mg/kg DOPS plus benserazide (neuronal density, 125 +/- 24 cells per millimeter) compared with the vehicle-treated ones (49 +/- 11 cells per millimeter) (P < .01). The immunoreactive NGF was greatly reduced from 3 hours after recirculation in the vehicle group, but it was much less reduced in the 300-mg/kg-DOPS-plus-benserazide group as compared with the vehicle group. The immunoreactivity for NGF receptor was gradually induced from 1 hour after recirculation with the peak at 1 day in the vehicle group, but it was only slightly induced at 8 hours in the 300-mg/kg-DOPS-plus-benserazide group. HSP70 immunoreactivity was also induced from 3 hours with the peak at 1 day in the vehicle group. However, in the 300-mg/kg-DOPS-plus-benserazide group, the induction of HSP70 was found from 8 hours and was much less intensive. Treatment with DOPS is protective to the ischemic hippocampal CA1 cells, and the NGF-receptor system may play a role in this protective effect of DOPS.

Free Radical Scavenging Action of Baicalein

TJ-960 is a Japanese Kampo (traditional herbal) medicine used for the treatment of epilepsy. It′s a crude drug, an extract of nine herbs, and consists of many known and unknown components. Among the known components of TJ-960, we found that 5,6,7-trihydroxy-2-phenyl-4 H-1-benzopyran-4-one (baicalein) might be the most potent scavenger for radicals. In the present study, we examined in vitro the radical scavenging effect of baicalein in detail using electron spin resonance spectrometry. Furthermore, we examined in vivo its effect on the thiobarbituric acid-reactive substances (TBARS) levels and superoxide dismutase in the brain of rats with FeCl 3-induced epilepsy and on hippocampal delayed neuronal death in gerbils with transient ischemia. In in vitro experiments, baicalein quenched in a dose-dependent manner 1,1-diphenyl-2-picrylhydrazyl, superoxide, and hydroxyl radicals. In the FeCl 3-induced epileptic model, baicalein suppressed the increase in the TBARS level at the FeCl 3-injected site. Baicalein also inhibited hippocampal neuronal death induced by 5 min of cerebral ischemia in gerbils. Hence the present study suggested that baicalein is one of the active components in TJ-960, which partially contributes to the antiepileptic and neuronal protective effects of TJ-960, and that the mechanism of its pharmacological action is based upon radical quenching and antioxidative effects.

Protective effect of bifemelane hydrochloride on ischemic hippocampal CA1 neuronal damage in the Gerbil: Relation to induction of HSP70

A protective effect of bifemelane hydrochloride (BF) on hippocampal CA1 neuronal death in gerbils was investigated following transient forebrain ischemia in relation to the induction of 70-kd heat shock protein (HSP70) and its mRNA. Histological examination showed that the neuronal density of the hippocampal CA1 sector treated with 10 and 30 mg/kg of BF (i.p.) was higher than that of the vehicle (p<0.05 and p<0.01, respectively) at 7 days after ischemia. Immunohistochemistry against HSP70 protein and in situ hybridization for the mRNA revealed that the inductions of immunoreactive HSP70 and the mRNA were remarkably reduced and limited in the brain hippocampi treated with BF (30 mg/kg) as compared with vehicle-treated animals. These data indicate that BF possesses a protective effect against ischemic injury to the vulnerable CA1 neurons. The possible mechanisms of the protection are discussed.

Effects of ketanserin and mianserin on delayed neuronal death induced by cerebral ischemia in Mongolian gerbils.

We examined whether ketanserin and mianserin, drugs with 5-HT2 receptor antagonistic effects, would have protective effects in Mongolian gerbils on delayed neuronal death induced by cerebral ischemia. When training and test sessions in the passive avoidance task were carried out 6 and 7 days after 3 min of ischemia, passive avoidance impairment was apparent. Destruction and disappearance was apparent in the hippocampal CA1 neurons at 7 days after the induced ischemia. Administration of ketanserin (5-20 mg/kg) and mianserin (5-20 mg/kg) led to better passive avoidance and prevented the delayed neuronal death induced by the ischemia. These effects of ketanserin and mianserin were not inhibited by treatment with the cholinergic blocker scopolamine (5 mg/kg). Thus, ketanserin and mianserin have a protective effect on delayed neuronal death in gerbils and the effects of these drugs are not mediated by serotonergic and cholinergic systems.

Protective effect of NGF atelocollagen mini-pellet on the hippocampal delayed neuronal death in gerbils

Very recently, contradictory results were presented as to the effects of exogenous nerve growth factor (NGF) on the hippocampal delayed neuronal necrosis following transient ischemia. In the present study, we administered a large amount of NGF with the atelocollagen mini-pellet system, measured the local NGF contents, and evaluated the effect of this neurotrophic factor on the postischemic hippocampal pyramidal cells in gerbils. We concluded that the exogenous NGF, when given continuously at sufficient concentrations, prevents pyramidal cell damage. The possible cause of discrepancy in previous studies is discussed.