Neuroprotective Effects In Rats Research Articles

Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats

Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood–brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

Intracerebral administration of ultrasound-induced dissolution of lipid-coated GDNF microbubbles provides neuroprotection in a rat model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Neurotrophic factors, such as glial cell derived neurotrophic factor (GDNF), have been shown to provide a neuroprotective effect in PD rats. We have previously reported that ultrasound-induced lipid-coated GDNF microspheres, which release GDNF in a sustained manner after low frequency ultrasound stimulation, can reduce hypoxic-ischemic injury in neonatal rats. In the present study, we investigated whether lipid-coated GDNF microspheres can provide a neuroprotective effect in a rat model of PD. After a rat model of PD was produced by 6-hydroxydompamine (6-OHDA) injections, lipid-coated GDNF microspheres (1.5mg/kg) were injected into the striatum of PD rats. We found that GDNF levels were increased in the striatum of PD rats after lipid-coated GDNF microspheres administration following low frequency ultrasound stimulation (20kHz, 5min per day, daily for 4 weeks). Moreover, GDNF microspheres reduced apomorphine-induced rotations, and increased striatal dopamine and nigral tyrosine hydroxylase (TH) levels in PD rats. Additionally, GDNF microspheres reduced caspase-3, tumor necrosis factor-alpha, matrix metalloproteinase 9 (MMP-9) and OX-6 levels induced by 6-OHDA injections in PD rats. These data indicated that lipid-coated GDNF microspheres can provide a neuroprotective effect in PD rats.

Neuroprotective effects of low dose minocycline against focal cerebral ischemia reperfusion injury in rats

Objective To investigate the neuroprotective effects of low dose intravenous minocycline against ischemia reperfusion injury in rats after focal cerebral ischemia reperfusion and to explore the possible mechanism.Methods Seventy-two rats were randomly divided into sham-operated group(S group),cerebral ischemia/reperfusion group(I/R group),and minocycline intervention group(I/R+ MC group).Focal cerebral ischemia was induced by filament medial cerebral artery occlusion method.Minocycline(3mg/kg)in saline was administered intravenously via the caudal vein twice a day for 14 days in the I/R+ MC group.At 2days after ischemia reperfusion,the infarct volume was evaluated using TTC staining,the permeability of blood-brain barrier was assessed by Evan's blue(EB)dye extravasation,and the expressions of high mobility group box-1protein(HMGB1)and Iba1,a marker of activated microglia,were analyzed by using Western blotting analysis.The neurological function recovery was evaluated using the modified neurological severity score(mNSS)at 2d,7d,and 14 d after ischemia/reperfusion.Results Two days after cerebral ischemia reperfusion,the brain infarction volume and the extravasations of EB were significantly increased and the expressions of HMGB1 and Iba1were significantly up-regulated in I/R group compared with sham group(P0.05).Compared with I/R group,minocycline at 3 mg/kg via the caudal veinsignificantly reduced the infarct volume in ischemic brain(P0.05),extravasation of EB and expressions of HMGB1 and Iba1(P0.05).Additionally,the rats in I/R+MC group exhibited a significantly decreased neurological severity score compared with I/R group(P0.05).Conclusion Minocycline exerts a neuroprotective effect in rats with cerebral ischemia reperfusion injury,which may be related to decrease of infarct size,inhibition of EB extravasation and microglia activation.

Is longer sevoflurane preconditioning neuroprotective in permanent focal cerebral ischemia?

Sevoflurane preconditioning has neuroprotective effects in the cerebral ischemia/reperfusion model. However, its influence on permanent cerebral ischemia remains unclear. In the present study, the rats were exposed to sevoflurane for 15, 30, 60, and 120 minutes, followed by induction of permanent cerebral ischemia. Results demonstrated that 30- and 60-minute sevoflurane preconditioning significantly reduced the infarct volume at 24 hours after cerebral ischemia, and 60-minute lurane preconditioning additionally reduced the number of TUNEL- and caspase-3-positive cells in the ischemic penumbra. However, 120-minute sevoflurane preconditioning did not show evident neuroprotective effects. Moreover, 60-minute sevoflurane preconditioning significantly attenuated neurological deficits and infarct volume in rats at 4 days after cerebral ischemia. These findings indicated that 60-minute sevoflurane preconditioning can induce the best neuroprotective effects in rats with permanent cerebral ischemia through the inhibition of apoptosis.

Improvement in Regional CBF by L-Serine Contributes to Its Neuroprotective Effect in Rats after Focal Cerebral Ischemia

To investigate the mechanisms underlying the neuroprotective effect of L-serine, permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery while monitoring cerebral blood flow (CBF). Rats were divided into control and L-serine-treated groups after middle cerebral artery occlusion. The neurological deficit score and brain infarct volume were assessed. Nissl staining was used to quantify the cortical injury. L-serine and D-serine levels in the ischemic cortex were analyzed with high performance liquid chromatography. We found that L-serine treatment: 1) reduced the neurological deficit score, infarct volume and cortical neuron loss in a dose-dependent manner; 2) improved CBF in the cortex, and this effect was inhibited in the presence of apamin plus charybdotoxin while the alleviation of both neurological deficit score and infarct volume was blocked; and 3) increased the amount of L-serine and D-serine in the cortex, and inhibition of the conversion of L-serine into D-serine by aminooxyacetic acid did not affect the reduction of neurological deficit score and infarct volume by L-serine. In conclusion, improvement in regional CBF by L-serine may contribute to its neuroprotective effect on the ischemic brain, potentially through vasodilation which is mediated by the small- and intermediate-conductance Ca2+-activated K+ channels on the cerebral blood vessel endothelium.

Combined treatment with celecoxib and sevoflurane after global cerebral ischaemia has no additive neuroprotective effects in rats

The purpose of this study was to investigate whether combined administration of celecoxib and sevoflurane after ischaemia produces additive neuroprotection against transient global cerebral ischaemia in rats. Cerebral ischaemia was induced by bilateral common carotid artery occlusion with haemorrhagic hypotension for 8 min. After ischaemia, no drugs were administered in the sham (n=4) and control (n=10) groups. In the celecoxib group (n=10), celecoxib 2 mg kg(-1) was administered after reperfusion. In the sevoflurane group (n=10), after reperfusion, sevoflurane 2.4% was inhaled two times for 5 min each at an interval of 10 min to achieve postconditioning. In the celecoxib+sevoflurane group (n=10), administration of celecoxib 2 mg kg(-1) and the sevoflurane postconditioning were performed simultaneously. Necrotic or apoptotic cells were examined in the hippocampus 7 days after ischaemia. Serum levels of proinflammatory cytokines including tumour necrosis factor-α and interleukin-1β were measured 2 h, and 3 and 7 days after ischaemia. Necrotic or apoptotic cells were observed more frequently in the control group than in the celecoxib or sevoflurane groups 7 days after ischaemia (P<0.05). Cytokine levels were higher in the control group when compared with the celecoxib or sevoflurane groups 2 h after ischaemia (P<0.05). However, the histological outcomes and cytokine levels were similar in all three groups treated with celecoxib or sevoflurane. Combined treatment with celecoxib and sevoflurane after global cerebral ischaemia has no additive neuroprotective effects in rats.

The Permeability of Puerarin Loaded Poly(butylcyanoacrylate) Nanoparticles Coated with Polysorbate 80 on the Blood–Brain Barrier and Its Protective Effect against Cerebral Ischemia/Reperfusion Injury

Puerarin (PUE) is a good candidate for treating stroke, but its low concentration in brain after administration limits its curative efficacy. The aim of the present work was to design and characterize PUE loaded poly(butylcyanoacrylate) nanoparticles (PBCN) coated with polysorbate 80 (Ps 80), and to evaluate the effect of PBCN on the permeability of PUE across the blood-brain barrier (BBB) and the effect of PUE loaded PBCN on the cerebral ischemia/reperfusion injury. PUE loaded PBCN were successfully prepared by anionic polymerization method with the mean particle size of 201.2 nm and the zeta potential of -7.72 mV. The in vitro release behavior of PUE from the nanoparticles showed a biphasic profile manner with an initial burst release followed by a sustained release. The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE loaded PBCN were both greater than these for the free drug. Moreover, compared with free drug, the vein injection of PUE loaded PBCN exerted the better neuroprotective effect in rats with focal cerebral ischemic injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, and reducing the infarct volume. The results indicated that this preparation may reduce the total dose required for the stroke therapy with concurrent reduction in dose related toxicity. All these findings suggest that PBCN could enhance the transport of PUE to brain and have a potential as a neuroprotective agent in the focal cerebral ischemic injury.

Preventive and Therapeutic Effects of Ginsenoside Rb1 for Neural Injury During Cerebral Infarction in Rats

To examine the preventive and therapeutic effects of ginsenoside Rb1 for neural injury during cerebral infarction, we used a middle cerebral artery occlusion (MCAO) model in rats to investigate the effects of ginsenoside Rb1 with Edaravone as a control. Ginsenoside Rb1 was given to the rats by intragastric administration either before or after the MCAO surgery to study its preventive and therapeutic effects. Ginsenoside Rb1-treated rats had a smaller infarct volume than the positive control. Interleukin-1 (IL-1), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), neurofilament (NF) and growth associated protein-43 (GAP-43) were measured to determine brain damage and the recovery of nerves. These findings suggest that ginsenoside Rb1 has neuroprotective effects in rats, and the protection efficiency is higher than Edaravone. The protective mechanism is different from Edaravone. The preventive ability of ginsenoside Rb1 is higher than its repair ability in neuroprotection in vivo.

Neuroprotective effect of granulocyte colony-stimulating factor in a focal cerebral ischemic rat model with hyperlipidemia

Granulocyte colony-stimulating factor (G-CSF) has been demonstrated to have neuroprotective effects in rat model with focal cerebral ischemia through anti-apoptotic pathways and by promoting proliferation of neural stem cells. In the present study, we examined the neuroprotective effect of G-CSF in an acute focal cerebral ischemia rat model with lipid metabolism disorder. Eighty male SD rats were randomly divided into normal diet control group (NC group) and high-fat diet group (HFD group) (n = 40 in each). In HFD group, rats were fed on high fat diet to induce atherosclerosis. After 29 days, 4 rats from each group were sacrificed to evaluate the effects of different diets, and the middle cerebral artery occlusion (MCAO) was performed in the rest of the rats. MCAO rats received either G-CSF (50 μg·kg(-1)·mL(-1)) or phosphate buffered saline (PBS) injection through the external jugular vein for 5 days, which was followed by 5-bromo-deoxy uridine (BrdU, i.p., 50 mg/kg) injection for another 7 days. To evaluate the effects of G-CSF treatment on neurological function, the modified neurological severity score (mNSS) was calculated. The vascular distribution, ischemic cells proliferation, cell apoptosis and the expression of vascular endothelial growth factor (VEGF) were measured to determine the effects of G-CSF treatment. Our results showed that G-CSF-treated rats had a lower mNSS than PBS-treated rats in both NC group and HFD group. G-CSF injection promoted endothelial cell proliferation and vascular regeneration, and inhibited cell apoptosis. The serum and tissue levels of VEGF were significantly increased after G-CSF treatment. It is concluded that G-CSF exerts its neuroprotective effect in focal cerebral ischemia rats with hyperlipidemia by enhancing angiogenesis, promoting cells proliferation, decreasing cell apoptosis, and increasing local VEGF expression.

Neuroprotective effect of 20(R)-ginsenoside Rg3 against transient focal cerebral ischemia in rats

Gensenosides, the active ingredients of Chinese herbal medicine Panax ginseng, have a wide spectrum of medical effects, such as anti-tumorigenic, angiosuppressive, adaptogenic, and anti-fatigue activities. In the present study, we have investigated the neuroprotective effect of 20(R)-ginsenoside Rg3 (20(R)-Rg3) against transient focal cerebral ischemia in male Sprague-Dawley (SD) rats. The middle cerebral artery was occluded for 2h in rats and then reperfused for 24h. The behavioral disturbance was evaluated according to neurological deficit scores, and the infarct volumes were evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining; in addition, ischemia-mediated apoptosis was examined using the method of terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP nick end labeling (TUNEL). The expressions of calpain I and caspase-3 mRNA in hippocampal CA1 region were further assayed using in situ hybridization, in order to clarify the neuroprotective mechanism of 20(R)-Rg3. 20(R)-Rg3 at the doses of 10 and 20mgkg−1 i.p., but not 5mgkg−1, showed significant neuroprotective effect in rats against focal cerebral ischemic injury by markedly reducing cerebral infarct volumes and degrading infarct rate of TTC-stained coronal brain sections, and improving behavior of the animals. Our results also suggested that 20(R)-Rg3 (10 and 20mgkg−1) could significantly suppress the expressions of calpain I and caspase-3 mRNA. These results indicated that 20(R)-Rg3 attenuates the neuronal apoptosis caused by cerebral ischemia–reperfusion injury and its neuprotective effect may be involved in the downregulation of calpain I and caspase-3.

Cytoprotective Effect of Hydroxytyrosyl Alkyl Ether Derivatives after Oral Administration to Rats in a Model of Glucose–Oxygen Deprivation in Brain Slices

This study was designed to determine whether the oral administration of hydroxytyrosol (HT) alkyl ether derivatives has a neuroprotective effect in rats. The animals were treated for 7 days with HT or ethyl, butyl, hexyl, octyl, and dodecyl HT ether. A method of in vitro hypoxia-reoxygenation in brain slices was used. Hexyl, octyl, and dodecyl HT derivatives reduced brain cell death (LDH efflux). Lipid peroxidation and nitrite concentrations were inhibited most by hexyl, octyl, and dodecyl derivatives. Concentrations of 3-nitrotyrosine were reduced by HT butyl, hexyl, octyl, and dodecyl ether derivatives. Interleukin-1β was significantly reduced in brain slices from rats treated with all HT ether derivatives. LDH efflux showed a linear correlation with brain concentrations of lipid peroxides, nitrites plus nitrates, and interleukin 1β. The reduction in oxidative and nitrosative stress and decreased production of pro-inflammatory interleukins may be the basis for the observed neuroprotective effects.

Enhanced neuroprotective effects for co-administration of g-csf with simvastatin on intracerebral hemorrhage in rats

Based on the neuroprotective effect of either G-CSF or statins in various neurological disease models, the purpose of this study was to evaluate the superiority of combined therapy G-CSF with simvastatin in experimental intracerebral hemorrhage (ICH). Primary ICH was induced in male Sprague Dawley rats. G-CSF (50 μg/kg), simvastatin (2 mg/kg), combined G-CSF and simvastatin, or phosphate buffered saline was given at 24 hours post-ICH. Neurobehavioral outcomes were assessed in all rats. The pathological changes of neuronal ultrastructure were examined with transmission electron microscopy at the given time. Simultaneously, immunohistochemical labeling and TUNEL assay were performed. Co-administration of G-CSF with simvastatin significantly promoted functional recovery and expedited the recovery time. Transmission electron microscopy revealed that combination treatment significantly improved ultrastructural outcomes. Histological examination showed that the expressions of Brdu co-labeled with NSE and GFAP, Factor VIII were higher in combined treatment than in control group. Additionally, the number of cell apoptosis was higher in control group than in experimental groups and lowest in combination group. Our results indicated that combination treatment of stroke with G-CSF and simvastatin augments the neuroprotective effect in rats after ICH.

Progesterone Produces Antinociceptive and Neuroprotective Effects in Rats with Microinjected Lysophosphatidic Acid in the Trigeminal Nerve Root

BackgroundIn our present study, we studied the role of demyelination of the trigeminal nerve root in the development of prolonged nociceptive behavior in the trigeminal territory.ResultsUnder anesthesia, the Sprague-Dawley rats were mounted onto a stereotaxic frame and 3 μL of lysophosphatidic acid (LPA, 1 nmol) was injected into the trigeminal nerve root to produce demyelination. This treatment decreased the air-puff thresholds, persisted until postoperative day 130, and then returned to the preoperative levels 160 days after LPA injection. The LPA-treated rats also showed a significant hyper-responsiveness to pin-prick stimulation. We further investigated the antinociceptive and neuroprotective effects of progesterone in rats undergoing demyelination of the trigeminal nerve root. Progesterone (8, 16 mg/kg/day) was administered subcutaneously, beginning on the operative day, for five consecutive days in the LPA-treated rats. Treatment with progesterone produced significant early anti-allodynic effects and delayed prolonged anti-allodynic effects. The expression of protein zero (P0) and peripheral myelin protein 22 (PMP22) were significantly down-regulated in the trigeminal nerve root on postoperative day 5 following LPA injection. This down-regulation of the P0 and PMP22 levels was blocked by progesterone treatment.ConclusionsThese results suggest that progesterone produces antinociceptive effects through neuroprotective action in animals with LPA-induced trigeminal neuropathic pain. Moreover, progesterone has potential utility as a novel therapy for trigeminal neuropathic pain relief at an appropriate managed dose and is therefore a possible future treatment strategy for improving the recovery from injury.

Effects of sevoflurane on neuronal cell damage after severe cerebral ischemia in rats

BackgroundThe aim of this study was to investigate the neuroprotective effects of sevoflurane after severe forebrain ischemic injury. We also examined the relationship between the duration of ischemia and neuronal cell death.MethodsMale Sprague-Dawley rats (300-380 g) were subjected to 6 (each n = 6) or 10 min (each n = 10) of near-complete forebrain ischemia while anesthetized with either 50 mg/kg of zoletil given intraperitoneally or inhaled sevoflurane (2.3%). Ischemia was induced by bilateral common carotid artery occlusion plus hemorrhagic hypotension (26-30 mmHg). Histologic outcomes were measured 7 days after ischemia in CA1 pyramidal cells of the rat hippocampus.ResultsThe mean percentage of necrotic cells in the hippocampal CA1 area decreased in the sevoflurane group compared to the zoletil group (25% vs. 40% after 6 min ischemia, respectively: P = 0.004 and 44% vs. 54% after 10 min of ischemia, respectively P = 0.03). The percentage of apoptotic cells was similar in all groups. The percentage of necrotic cells in each anesthetic groups was significantly higher in the 10 min ischemia group compared to the 6 min ischemia group (P = 0.004 in the sevoflurane group, P = 0.03 in the zoletil group).ConclusionsThe present data show that sevoflurane has neuroprotective effects in rats subjected to near-complete cerebral ischemia. Longer duration of ischemia is associated with more neuronal injury when compared to ischemia of shorter duration.

Neuroprotective effect of pyruvate and oxaloacetate during pilocarpine induced status epilepticus in rats

Recent research data have shown that systemic administration of pyruvate and oxaloacetate causes an increased brain-to-blood glutamate efflux. Since increased release of glutamate during epileptic seizures can lead to excitotoxicity and neuronal cell death, we tested the hypothesis that glutamate scavenging mediated by pyruvate and oxaloacetate systemic administration could have a neuroprotective effect in rats subjected to status epilepticus (SE). SE was induced by a single dose of pilocarpine (350mg/kgi.p.). Thirty minutes after SE onset, a single dose of pyruvate (250mg/kgi.p.), oxaloacetate (1.4mg/kgi.p.), or both substances was administrated. Acute neuronal loss in hippocampal regions CA1 and hilus was quantitatively determined five hours after SE onset, using the optical fractionator method for stereological cell counting. Apoptotic cascade in the hippocampus was also investigated seven days after SE using caspase-1 and -3 activity assays. SE-induced neuronal loss in CA1 was completely prevented in rats treated with pyruvate plus oxaloacetate. The SE-induced caspase-1 activation was significantly reduced when rats were treated with oxaloacetate or pyruvate plus oxaloacetate. The treatment with pyruvate and oxaloacetate caused a neuroprotective effect in rats subjected to pilocarpine-induced SE.

Inhibition of nuclear factor-κB by 6-O-acetyl shanzhiside methyl ester protects brain against injury in a rat model of ischemia and reperfusion

BackgroundRecent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti-inflammatory drugs in cerebral ischemia have been documented. When screening natural compounds for drug candidates in this category, we isolated 6-O-acetyl shanzhiside methyl ester (ND02), an iridoid glucoside compound, from the leaves of Lamiophlomis rotata (Benth.) Kudo. The objectives of this study were to determine the effects of ND02 on a cultured neuronal cell line, SH-SY5Y, in vitro, and on experimental ischemic stroke in vivo.MethodsFor TNF-α-stimulated SH-SY5Y cell line experiments in vitro, SH-SY5Y cells were pre-incubated with ND02 (20 μM or 40 μM) for 30 min and then incubated with TNF-α (20 ng/ml) for 15 min. For in vivo experiments, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion for 23 h.ResultsND02 treatment of SH-SY5Y cell lines blocked TNF-α-induced nuclear factor-κB (NF-κB) and IκB-α phosphorylation and increased Akt phosphorylation. LY294002 blocked TNF-α-induced phosphorylation of Akt and reduced the phosphorylation of both IκB-α and NF-κB. At doses higher than 10 mg/kg, ND02 had a significant neuroprotective effect in rats with cerebral ischemia and reperfusion (I/R). ND02 (25 mg/kg) demonstrated significant neuroprotective activity even after delayed administration 1 h, 3 h and 5 h after I/R. ND02, 25 mg/kg, attenuated histopathological damage, decreased cerebral Evans blue extravasation, inhibited NF-κB activation, and enhanced Akt phosphorylation.ConclusionThese data show that ND02 protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and that these protective effects may be due to blocking of neuronal inflammatory cascades through an Akt-dependent NF-κB signaling pathway.

VEGF Infusion and Rearing in Enriched Environments During the Visual Critical Period Have Neuroprotective Effects in Rats

VEGF Infusion and Rearing in Enriched Environments During the Visual Critical Period Have Neuroprotective Effects in Rats

Mild Systemic Inflammation has a Neuroprotective Effect After Stroke in Rats

Stroke is accompanied by a strong inflammatory reaction in the brain. Periodontal disease is a chronic local infection which causes a systemic low grade inflammation. We hypothesized that a mild systemic inflammatory reaction as caused by periodontal disease prior to stroke onset, may exert a neuroprotective effect in a rat model of focal ischemia. To test this hypothesis, marginal periodontitis was induced by ligatures on the second maxillary molars in BB/LL Wistar rats for 3 weeks. Two weeks after periodontitis initiation, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery. After a survival time of 7 days after ischemia, rats were killed and bone loss was determined on the buccal and palatinal surfaces of the defleshed jaw. In addition, markers of systemic inflammation were determined in a different group of laboratory animals at 14 days after the onset of periodontitis. The infarct size and markers of the inflammatory reaction in the brain were determined by immunohistochemistry. We found: (i) rats with ligatures exhibited significantly more periodontal bone loss than the control rats; (ii) the development of periodontitis was associated with an elevated gene expression for several markers of systemic inflammation (interleukin-10, transforming growth factor beta 1, tumor necrosis factor alpha, interleukin-1beta and interferon gamma; (iii) rats with periodontitis and a mild systemic inflammation had a significantly reduced infarct volume and a significant reduction in the number of brain macrophages in the infarcted area. In conclusion we found that mild systemic inflammation elicited prior to stroke onset may have a neuroprotective effect in rats by reducing the infarct volume and tissue destruction by brain macrophages.

Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia–reoxygenation

Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are two well-known phenolic compounds with antioxidant properties that are present in virgin olive oil (VOO). Because VOO has shown neuroprotective effects in rats, the purpose of the present study was to investigate the possible neuroprotective effect of HT and HT-AC in a model of hypoxia–reoxygenation in rat brain slices after in vitro incubation of these compounds or after 7 days of oral treatment with 5 or 10 mg/kg per day. Lactate dehydrogenase (LDH) efflux to the incubation medium was measured as a marker of brain cell death. HT and HT-AC inhibited LDH efflux in a concentration-dependent manner, with 50% inhibitory concentrations of 77.78 and 28.18 μM, respectively. Other well-known antioxidants such as vitamin E and N-acetyl-cysteine had no neuroprotective effect in this experimental model. After 1 week of treatment, HT (5 and 10 mg/kg per day p.o.) reduced LDH efflux by 37.8% and 52.7%, respectively, and HT-AC reduced LDH efflux by 45.4% and 67.8%. These data are additional evidence of the cytoprotective effect of VOO administration, and provide a preliminary basis for further study of these polyphenols as potential neuroprotective compounds.

Ibuprofen protects ischemia-induced neuronal injury via up-regulating interleukin-1 receptor antagonist expression

The inflammatory response accompanies and exacerbates the developing injury after cerebral ischemia. Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to attenuate injuries in animal models of various neurological diseases. In the present study, we investigated ibuprofen’s neuroprotective effects in rats exposed to transient forebrain ischemia and in cultures exposed to oxygen glucose deprivation (OGD). Rats treated with ibuprofen after transient forebrain ischemia displayed long-lasting protection of CA1 hippocampal neurons. There were selective increases in interleukin-1 receptor antagonist gene and protein expression in ibuprofen-treated OGD microglia. Furthermore, treatment with ibuprofen in neuron/microglia co-cultures increased the number of surviving HC2S2 neurons against OGD whereas IL-1ra neutralizing antibody reversed the ibuprofen-induced neuroprotection. The data indicate that ibuprofen-induced IL-1ra secretion is involved in neuroprotection against ischemic conditions.