Transient Focal Ischemia In Rats Research Articles

Acute iron overload aggravates blood-brainbarrier disruption and hemorrhagic transformation after transient focal ischemia in rats with hyperglycemia.

Hemorrhagic transformation (HT) has been reported to be associated with a poor prognosis after acute ischemic stroke. Blood-brain barrier (BBB) damage is considered as the major pathophysiologic mechanism of HT. Our aim was to investigate the role of acute iron overload in BBB damage and HT after transient focal ischemia in rats with hyperglycemia. Transient middle cerebral artery occlusion (MCAO) was induced in rats with hyperglycemia. Animals were assigned to four groups: Sham, Vehicle, Iron overload and Iron chelator treatment groups. Brain samples were collected at 24 h after surgery to quantify the amount of hemorrhage, determine extravasation of Evans blue and detect the levels of following proteins: ferritin, matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), Occludin and Claudin-5 by western blot analysis and immunohistochemistry. Compared to the Vehicle group, the Iron overload group had a significantly higher amount of hemorrhage and more extravasation of Evans blue. The Iron overload group had lower levels of ZO-1, Occludin and Claudin-5 and higher levels of ferritin and MMP-9 than the Vehicle group. Administering iron chelator reduced the extension of hemorrhage and extravasation of Evans blue, reversed the MCAO-induced reduction of ZO-1, Occludin and Claudin-5 and decreased the levels of ferritin and MMP-9. Our results suggest that acute iron overload aggravates BBB damage and HT after transient ischemia in rats with hyperglycemia, which provides basic evidence for iron overload as a potential factor associated with BBB damage and HT in ischemic stroke patients when accompanied with hyperglycemia.

Neuroprotective efficacy of N-t-butylhydroxylamine (NtBHA) in transient focal ischemia in rats.

The pharmacological or toxicological activities of the degradation products of drug candidates have been unaddressed during the drug development process. Ischemic stroke accounts for 80% of all strokes and is responsible for considerable mortality and disability worldwide. Despite decades of research on neuroprotective agents, tissue plasminogen activators (t-PA), a thrombolytic agent, remains the only approved acute stroke pharmacological therapy. NXY-059, a free radical scavenger, exhibited striking neuroprotective properties in preclinical models and met all the criteria established by the Stroke Academic Industry Roundtable (STAIR) for a neuroprotective agent. In phase 3 clinical trials, NXY-059 exhibited significant neuroprotective effects in one trial (SAINT-I), but not in the second (SAINT-II). Some have hypothesized that N-t-butyl hydroxylamine (NtBHA), a breakdown product of NXY-059 was the actual neuroprotective agent in SAINT-I and that changes to the formulation of NXY-059 to prevent its breakdown to NtBHA in SAINT -II was the reason for the lack of efficacy. We evaluated the neuroprotective effect of NtBHA in N-methyl-D-aspartate (NMDA)-treated primary neurons and in rat focal cerebral ischemia. NtBHA significantly attenuated infarct volume in rat transient focal ischemia, and attenuated NMDA-induced cytotoxicity in primary cortical neurons. NtBHA also reduced free radical generation and exhibited mitochondrial protection.

Acute iron overload aggravates blood brain barrier disruption and hemorrhagic transformation after transient focal ischemia in rats with hyperglycemia

We aimed to verify whether acute intracerebral iron overload aggravates blood-brain barrier (BBB) damage and hemorrhagic transformation (HT) after transient focal ischemia in rats with hyperglycemia and deferoxamine (DFX) maintains the integrity of BBB and reduces a risk of HT.

Response of distant regions affected by diaschisis commissuralis in one of the most common models of transient focal ischemia in rats

Stroke induces widespread changes in the brain. In this paper, we monitored some markers of early (2 h) and delayed events (1, 3 and 7 days of reperfusion) initiated by middle cerebral artery occlusion in core/penumbra counterparts of the non-ischemic hemisphere (i.e. contra-core and contra-penumbra).Our results showed that a profound transient drop (2 h and 3 days) of protein synthesis was measured in the contra-core, while the contra-penumbra exhibited translation over-activity at the same time. Glutamate release was detected only in the contra-core, with a peak on the first day. Degenerating neurons became visible in the striatum (day 1), followed by cortex (day 3), earlier in contra-penumbra and later in contra-core. Moreover, the loss of NADPH diaphorase-positive neurons in the non-ischemic hemisphere was detected, with the greatest drop at the first day. Total microglia also started to fall, the earliest in the contra-penumbra region of the striatum (day 1), followed by the contra-core of the striatum and both cortex regions at the seventh day.In conclusion, transient focal ischemia affects remote regions of the brain and initiates processes involved in neuronal degeneration in an order which corresponds to the tissue sensitivity to ischemia, namely earlier in the contra-penumbra, and afterwards in the contra-core. The mechanism of secondary damage would influence the progressive neuronal loss of more distant brain regions.

Comparative analysis of gonadal steroid-mediated neuroprotection after transient focal ischemia in rats: route of application and substrate composition.

Progesterone (P) and 17ß-estradiol (E2) mitigate neuronal damage after experimentally induced traumatic brain injury (TBI) and ischemic stroke. Fish oil components such as omega-3 polyunsaturated fatty acids (PUFA n3) also provide neuroprotection in these traumatic models. Steroids and PUFA n3 dampen neuroinflammatory processes and regulate glial function in the affected brain areas. Using a transient focal ischemic rat model, we demonstrate that the co-application of PUFA n3 and P/E2 and the choice of the application route have a clear impact on the prevention of ischemia-induced infarct volume and behavioral recovery. A combinatory PUFA n3 plus P/E2 emulsion intravenously administered was most effective in reducing the infarct size and in restoring behavioral reconstitution compared to other oil emulsions and subcutaneous depot medication. These data encourage to refining clinical treatment protocols for TBI and stroke with gonadal steroids and to establishing combinatory drugs of steroids and fish oil-enriched emulsions thereby creating a win-win situation with two effective components.

Electrical stimulation of the vagus nerve dermatome in the external ear is protective in rat cerebral ischemia.

Although cervical vagus nerve stimulation is effective for reducing infarct volume in rats, it is not feasible for acute human stroke as it requires surgical incision of the neck. We hypothesized that stimulation of the dermatome in the external ear innervated by the vagus nerve (auricular vagus nerve stimulation; aVNS) reduces infarct volume after transient focal ischemia in rats. Animals were randomized to active aVNS or sham stimulation. For aVNS, electrical stimulation of the left cavum concha (1h duration) using percutaneous needles was initiated 30min after induction of ischemia. Behavioral and tissue outcome were measured 24h after induction of ischemia. In a separate experimental dataset, c-Fos immunohistochemistry was performed to identify the brain regions activated after the stimulation. Stimulation of the left cavum concha resulted in bilateral c-Fos staining in the nuclei tractus solitarii and the loci coerulei in all animals. There was no c-Fos staining in any part of the brainstem in sham control animals. The mean infarct volume (SD) as calculated by indirect method was 44.20±7.58% in controls and 31.65±9.67% in treated animals (P<0.0001). The effect of aVNS on tissue outcome was associated with better neurological scores at 24h after ischemia (P<0.0001). Electric stimulation of the vagus nerve dermatome in the external ear activates brainstem afferent vagal nuclei and reduces infarct volume in rats. This finding has potential to facilitate the development of treatments that leverage the brain's endogenous neuroprotective pathways at the setting of acute ischemic stroke.

Brain remodelling following endothelin-1 induced stroke in conscious rats.

The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76–77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.

Abstract 171: Effect of Long-Term Treatment With Fimasartan on Transient Focal Ischemia in Rat Brain

Background and purpose: Fimasartan is a novel angiotensin receptor blocker (ninth), and its safety and efficacy have been established as an antihypertensive drug. Anti-apoptotic or anti-inflammatory effects of angiotensin receptor blockers were reported. However, few studies have elaborated on the effects of long-term treatment with low-dose ARB on cerebral ischemia independent of blood pressure lowering. Methods: Noninvasive blood pressure monitoring was performed in Sprague-Dawley rats which 0.5 mg/kg of fimasartan or phosphate-buffered saline (PBS) were administered for 4 weeks. Fimasartan (0.5, 1 or 3 mg/kg) was administered intraorally for 4 weeks, and we induced ischemia-reperfusion injury in rats. Infarct volume and the number of TUNEL-positive apoptotic cells were measured at 7 days. Functional outcomes were evaluated by modified limb placing test. To identify the anti-inflammatory effect of fimasartan, the number of inflammatory cells (OX6-positive cells) was measured. To identify mediators, phospho-STAT3 and IkB proteins were measured via Western blot analyses at 48 hours. Results: Blood pressures were decreased after administration of 1 mg/kg or 3 mg/kg of fimasartan for 4 weeks, but were not decreased in 0.5 mg/kg group. All doses of fimasartan decrease infarct volumes, and low-dose fimasartan (0.5 mg/kg) maximally reduced infarct volume up to 70% of those of the control group ( p &lt; 0.05). Quantitative analysis showed that the number of TUNEL-positive cells was remarkably decreased in the low-dose fimasartan group (622 ± 57 cell/mm 3 vs. 235 ± 48 cells/mm 3 ; p &lt; 0.05). Low-dose fimasartan improved functional outcomes at 14 days (74% recovery in fimasartan group vs. 43% in control group; p &lt; 0.05). The low-dose fimasartan group exhibited a lower number of OX6-positive cells (fimsartan group: 157 ± 17 cells/mm 3 ; control: 86 ± 11 cell/mm 3 ; p &lt; 0.05). The IkB degradation as a marker of NF-kB activation, was delayed, and phospho-STAT3 was decreased in the low-dose fimasartan group ( p &lt; 0.05). Conclusion: We demonstrate that long-term treatment with fimasartan improves neurological outcome in transient focal ischemia in rats. This protective effect of fimasartan is independent blood pressure lowering.

Continuous oral administration of atorvastatin ameliorates brain damage after transient focal ischemia in rats

AimsPre-treatment with statins is known to ameliorate ischemic brain damage after experimental stroke, and is independent of cholesterol levels. We undertook pre- vs post-ischemic treatment with atorvastatin after focal cerebral ischemia in rats. Main methodsMale Sprague–Dawley rats underwent transient 90-min middle cerebral artery occlusion (MCAO). Atorvastatin (20mg/kg/day) or vehicle was administered orally. Rats were divided into vehicle-treated, atorvastatin pre-treatment, atorvastatin post-treatment, and atorvastatin continuous-treatment groups. In the pre-treatment, rats were given atorvastatin or vehicle for 7days before MCAO. In the post-treatment, rats received atorvastatin or vehicle for 7days after MCAO. Measurement of infarct volume, as well as neurological and immunohistochemical assessments, were done 24h and 7days after reperfusion. Key findingsEach atorvastatin-treated group demonstrated significant reductions in infarct and edema volumes compared with the vehicle-treated group 24h after reperfusion. Seven days after reperfusion, infarct volumes in the post-treatment group and continuous-treatment group (but not the pre-treatment group) were significantly smaller than in the vehicle-treated group. Only the continuous-treatment group had significantly improved neurological scores 7days after reperfusion compared with the vehicle group. Post-treatment and continuous-treatment groups had significantly decreased lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha, and neuronal damage in the cortical ischemic boundary area after 7days of reperfusion. SignificanceThese results suggest that continuous oral administration (avoiding withdrawal) with statins after stroke may reduce the extent of post-ischemic brain damage and improve neurological outcome by inhibiting oxidative stress and inflammatory responses.

Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats

Normobaric oxygen (NBO) reduces infarction at 24–48h in experimental models of focal cerebral ischemia. However, to be clinically relevant, longer term safety and efficacy must be explored. Here, we assessed the effects of NBO on glial activation, neurovascular recovery, and behavioral outcomes at 2weeks after transient focal ischemia in rats. 100min transient focal ischemia was induced by intraluminal occlusion of the middle cerebral artery in adult male Sprague–Dawley rats. Animals were randomized into sham, controls or 85′NBO started 15min after ischemic onset. Infarct volumes and behavioral outcomes were blindly quantified. Immunohistochemistry was used to examine the effects of NBO on glial activation and neurovascular responses. After 2weeks of reperfusion the infarct volume was marked reduced in animals subjected to NBO. They also had better outcomes in forelimb placement test and in body-swing test and weight loss reduction. After 14days, NBO decreased expression of Iba1, a marker of activated microglia, and GFAP, a marker of activated astrocytes. NBO treatment had no detectable effect on angiogenesis. These results suggest that protective effects of NBO may persist for up to 2weeks post-stroke.

Neuroprotective properties of antioxidants in stroke correlate with their effects on ischemic release of glutamate

Antioxidant agents potently protect against ischemic brain damage in animals, but show no clinical benefits in humans. In the present study we tested the hypothesis that potency of antioxidants in preventing pathological glutamate release can predict their ability to reduce ischemic infarction. Transient focal ischemia in rats was induced by 2‐hr occlusion of the middle cerebral artery. Antioxidants Tempol and Edaravone (500 nmols) were injected into the lateral ventricles prior to ischemia. 72 hrs later, control and antioxidant‐treated animals were evaluated for behavioral deficits and brain damage. Tempol, but not Edaravone, reduced infarction volumes by ~60% and improved neurological outcomes. In parallel microdialysis experiments, Tempol but not Edaravone reduced extracellular levels of the excitatory neurotransmitter glutamate. Paradoxically, when tested in antioxidant assays in vitro, Edaravone was more effective in scavenging the majority of the ischemia related free radicals and oxidants. The only exception was scavenging of superoxide anion, in which Tempol was superior to Edaravone. Overall, these results suggest that neuroprotective properties of Tempol are determined by its ability to scavenge superoxide and prevent pathological glutamate release.

Ginsenoside Rd blocks AIF mitochondrio-nuclear translocation and NF-κB nuclear accumulation by inhibiting poly(ADP-ribose) polymerase-1 after focal cerebral ischemia in rats

Our previous clinical and basic studies have demonstrated that ginsenoside Rd (GS-Rd) has remarkable neuroprotective effects after cerebral ischemia but the underlying mechanisms are still unknown. In our latest studies, we revealed that GS-Rd could prevent mitochondrial release of apoptosis-inducing factor (AIF) and reduce inflammatory response following transient focal ischemia in rats. Poly(ADP-ribose) polymerase-1 (PARP-1) is required for both AIF release from mitochondria and NF-κB-mediated inflammation. Here, we investigated whether GS-Rd could act on PARP-1 and subsequently affect AIF translocation and NF-κB activation. Sprague-Dawley rats were treated with GS-Rd (10 mg/kg) 30 min before surgery with the right middle cerebral artery occlusion, and at different time points following cerebral ischemia, brain tissues were collected for western blotting analysis. Our results showed that GS-Rd significantly attenuated ischemia-triggered increased levels of Poly(ADP-ribose), an enzymatic product catalyzed by PARP-1, but not altered the expression of PARP-1 per se. Meanwhile, GS-Rd pretreatment reduced AIF mitochondrio-nuclear translocation and inhibited NF-κB p65 subunit nuclear accumulation after cerebral ischemia. Therefore, our findings provide the first evidence that GS-Rd can inhibit PARP-1 activity and sequential AIF translocation and NF-κB nuclear accumulation, which may be responsible for GS-Rd's neuroprotection against both neuronal cell death and inflammation after ischemic stroke.

Effects of stromal cell-derived factor 1α delivered at different phases of transient focal ischemia in rats

Endogenous stromal cell-derived factor 1α (SDF1α) has been implicated in postischemic tissue repair, suggesting SDF1α as a potential therapeutic molecule to treat stroke patients. In spite of its potential, no data are available regarding the short- and long-term effects of SDF1α when it is delivered at different phases of stroke. In our study, adenovirus expressing SDF1α gene (AV-SDF1α) was introduced into the boundary of the infarcted area either 3 days before or 1 week after ischemia, and behavioral performance was measured over 5 weeks. Immediate behavioral and structural amelioration was evident when AV-SDF1α was injected 3 days before ischemia, which might be the result of SDF1α-mediated neuroprotection as supported by the TUNEL staining and Western blot analysis of active caspase-3. In addition, increase in neurogenesis, neuroblast migration, and neural differentiation was also apparent in the AV-SDF1α-injected brain, which contributed to further amelioration at later time points (“delayed response”). On the contrary, when AV-SDF1α was introduced 1 week post-ischemia (in the subacute phase), significant behavioral recovery became apparent beginning 5 weeks after viral delivery. Taken together, the therapeutic efficacy of SDF1α varied considerably depending on when SDF1α overexpression was initiated; initiating SDF1α overexpression before ischemia exerted both immediate and delayed beneficial effects, whereas initiating overexpression in the subacute phase exerted only a delayed response.

Korean red ginseng protects against neuronal damage induced by transient focal ischemia in rats

In the present study, we investigated the neuroprotective effect of Korean red ginseng (KRG) following focal brain ischemia/reperfusion injury, in relation to its antioxidant activities. The middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats was employed. The KRG extract (100 mg/kg, perorally) was administered once daily for 7 days following MCAO/R. The elevated levels of lipid peroxidation in the MCAO/R group were attenuated significantly in the KRG-administered group. The significantly depleted activity of the antioxidant enzymes glutathione peroxidase, superoxide dismutase and catalase was prevented in the KRG-administered group. In the neurobehavioral evaluation expressed as the modified neurological severity score and corner-turn test, the daily intake of KRG showed consistent and significant improvement in the neurological deficits for 7 days following MCAO/R injury. These results indicate that KRG has a neuroprotective effect against ischemia/reperfusion brain injury by reducing the level of lipid peroxidation and increasing the endogenous antioxidant enzymatic activity.

Effects of tetrahydrobiopterin on cerebral infarction after transient focal ischemia in rats

Objectives: The present study investigated the effects of tetrahydrobiopterin (BH4) on cerebral infarction after transient focal ischemia in rats.Methods: Focal ischemia (1·5 hours) was created in male Sprague-Dawley rats (250-280 g) by middle cerebral artery occlusion. Some rats were treated with 20 mg/kg tetrahydrobiopterin by intraperitoneal injection 30 minutes before reperfusion. At 2, 6, and 12 hours of reperfusion, the brains were harvested for the nitric oxide synthase (NOS) activity and nitric oxide (NO) level assays. At 12 hours of reperfusion, the brains were harvested for infarct size measurement.Results: NOS activity and NO level were all augmented after reperfusion. BH4 treatment significantly further increased NOS activity and NO level. Cerebral infarct size was significantly bigger in BH4 treatment group compared to that in no treatment group.Conclusions: The data indicate that BH4 enhances cerebral infarction after transient focal ischemia in rats, through NOS and NO pathway.

Neuroprotective Effects and Suppression of Ischemia-induced Glutamate Elevation by β1-Adrenoreceptor Antagonists Administered Before Transient Focal Ischemia in Rats

β-Adrenoreceptor antagonists provide neuroprotective effects after focal cerebral ischemia in experimental settings. This study was conducted to compare the neuroprotective effects of low-dose and high-dose of selective β1-adrenoreceptor antagonists in rats after focal cerebral ischemia. We also investigated whether glutamate and norepinephrine contribute to neuroprotection of the β-adrenoreceptor antagonists. Sprague-Dawley rats were subjected to 120 minutes middle cerebral artery occlusion. The rats received intravenous infusion of saline 0.5 mL/h, esmolol 200, esmolol 2000, landiolol 50, or landiolol 500 μg/kg/min. Infusion of all the drugs were started 30 minutes before ischemia and continued for 24 hours. Neurological deficit scores were evaluated at 1, 4, and 7 days, whereas the brains were removed and stained at 7 days after ischemia. In the esmolol 200, and landiolol 50 μg/kg/min groups of additional rats, glutamate and norepinephrine concentrations in the striatum were measured separately by microdialysis during ischemia (glutamate, 120 min; norepinephrine, 110 min) and reperfusion (40 min). Neurological deficit scores were smaller in rats treated with esmolol or landiolol than in saline-treated rats at 1, 4, and 7 days. The cortical and striatal infarct volumes were smaller in rats receiving β-adrenoreceptor antagonists than in the saline-treated rats. There were no significant differences in neurological score or infarct volume between the groups receiving the different doses of β1-adrenoreceptor antagonists. The area under the curve of glutamate in the esmolol-treated or landiolol-treated rats was significantly smaller than that in the saline-treated rats, whereas no significant differences were noted in the norepinephrine concentration among the groups. This study indicates that the improvement in neurological and histologic outcomes by selective β1-adrenoreceptor antagonists after transient focal cerebral ischemia is partly attributed to attenuation of glutamate release.

Ginsenoside Rd attenuates early oxidative damage and sequential inflammatory response after transient focal ischemia in rats

We previously found that ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, attenuates neuronal oxidative damage in vitro induced by hydrogen peroxide and oxygen–glucose deprivation. In this study, we sought to investigate the potential protective effects and associated mechanisms of Rd in a rat model of focal cerebral ischemia. Rats administered with Rd (0.1–200mg/kg) or vehicle was subjected to transient middle cerebral artery occlusion. Rd at the dose of 10–50mg/kg significantly reduced the infarct volume and improved the long-term neurological outcome up to 6 weeks after ischemia. To evaluate the underlying mechanisms, in vivo free radical generation was monitored using microdialysis, oxidative DNA damage was identified by 8-hydroxy-deoxyguanosine immunostaining, oxidative protein damage was identified by the assessment of protein carbonyl and advanced glycosylation end products, and lipid peroxidation was estimated by determining the malondialdehyde and 4-hydroxynonenal formations. Microdialysis results displayed a prominent inhibitory effect of Rd on the hydroxy radical formation trapped as 2,3- and 2,5-DHBA. Early accumulations of DNA, protein and lipid peroxidation products were also suppressed by Rd treatment. Although Rd partly preserved endogenous antioxidant activities in the ischemic penumbra, in sham rats without stroke, endogenous antioxidant activities were not affected by Rd. Furthermore, we assayed sequential inflammatory response in a later phase after ischemia. Rd significantly eliminated inflammatory injury as indicated by the suppression of microglial activation, inducible nitric oxide synthase and cyclooxygenase-2 expression. Collectively, these findings demonstrated that Rd exerts neuroprotection in transient focal ischemia, which may involve early free radicals scavenging pathway and a late anti-inflammatory effect.

Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

Khat affects apoptosis and related gene XIAP and Smac expression following transient focal ischemia in rats

Khat affects apoptosis and related gene XIAP and Smac expression following transient focal ischemia in rats

Damage to Neurons and Oligodendrocytes in the Hippocampal CA1 Sector after Transient Focal Ischemia in Rats

Focal brain lesions such as transient focal cerebral ischemia can lead to neuronal damage in remote areas, including the ipsilateral substantia nigra and hippocampus, as well as in the ischemic core. In this study, we investigated acute changes in the ipsilateral hippocampus from 1 up to 7days after 90min of transient focal cerebral ischemia in rats, using anti-NeuN (neuronal nuclei), anti-Cu/Zn-superoxide dismutase (Cu/Zn-SOD), anti-Mn-SOD, anti-neuronal nitric oxide synthase (nNOS), anti-inducible NOS (iNOS), anti-glial fibrillary acidic protein (GFAP), anti-ionized calcium-binding adaptor molecule 1(Iba 1) and anti-2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) antibodies. In our western blot and histochemical analyses, present results show that transient focal cerebral ischemia in rats can cause a severe and acute damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector. The present findings also demonstrate that the expression of iNOS produced by Iba 1-immunopositive microglia precedes the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia. In contrast, our results suggest that increased reactive oxygen species (ROS) production during reperfusion cannot lead to damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia, because of an insufficient expression of Cu/Zn-SOD and Mn-SOD. Our double-labeled immunohistochemical study demonstrates that the overexpression of iNOS produced by Iba 1-immunopositive microglia may play a pivotal role in the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector at an acute stage after transient focal cerebral ischemia.