Development Of Neuronal Injury Research Articles

Neuropharmacological Effects of Quercetin: A Literature-Based Review

Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimer’s disease, Amyloid β peptide, Parkinson’s disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.

Altered endothelial nitric oxide synthesis in preterm and small for gestational age infants

Preterm infants are often exposed to neuronal and endothelial damage. The aim of the present study was to investigate the correlation between endothelial dysfunction and neuronal injury in preterm infants. We compared serum nitric oxide (NO), endothelial nitric oxide synthase (eNOS) and neuron-specific enolase (NSE) concentrations in 33 moderate preterm (MP) and 47 late preterm (LP) infants using standard ELISA. Each group was classified as appropriate for gestational age (AGA) or small for gestational age (SGA). Compared to the AGA infants, the SGA infants had higher NO on day 1 (MP: mean, 72.3 ng/mL, range, 50.9-99.5 ng/mL vs 52.2 ng/mL, range, 28.1-68.2 ng/mL, P < 0.05; LP: mean, 58.4 ng/mL, range, 25.7-66.4 ng/mL vs 43.7 ng/mL, range, 21.2-60.6 ng/mL, P < 0.05), lower eNOS concentration on day 3 in the MP group (mean, 5.8 IU/mL, range, 1.2-7.9 IU/mL vs 8.9 IU/mL, range, 4.2-14.6 IU/mL, P < 0.05), and on day 1 in the LP group (mean, 5.5 IU/mL, range, 1.5-8.1 IU/mL vs 7.7 IU/mL, range, 4.4-13.8 IU/mL, P < 0.05). The NO/eNOS ratio was higher in SGA infants compared with the AGA subgroups (MP: mean, 13.8, range, 9.9-20.2 vs mean, 9.9, range, 4.7-13.1, P < 0.05; LP: mean, 12.2, range, 9.2-19.9 vs mean, 9.9, range, 5.4-14.4, P < 0.05). AGA infants had lower NSE concentration compared with the SGA infants on day 1 in the LP group (mean, 27.4 ng/mL, range, 20-43 ng/mL vs mean, 40.89 ng/mL, range, 34-51 ng/mL, P < 0.05). A positive correlation was found between NO/eNOS ratio and NSE concentration (r = 0.75, P < 0.05 and r = 0.64, P < 0.05 on days 1 and 3, respectively). High NO concentration in the context of low eNOS activity suggests a possible role of NO in the development of neuronal injury in SGA infants.

Autoantibodies to Nervous System-Specific Proteins Are Elevated in Sera of Flight Crew Members: Biomarkers for Nervous System Injury

This descriptive study reports the results of assays performed to detect circulating autoantibodies in a panel of 7 proteins associated with the nervous system (NS) in sera of 12 healthy controls and a group of 34 flight crew members including both pilots and attendants who experienced adverse effects after exposure to air emissions sourced to the ventilation system in their aircrafts and subsequently sought medical attention. The proteins selected represent various types of proteins present in nerve cells that are affected by neuronal degeneration. In the sera samples from flight crew members and healthy controls, immunoglobin (IgG) was measured using Western blotting against neurofilament triplet proteins (NFP), tubulin, microtubule-associated tau proteins (tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and glial S100B protein. Significant elevation in levels of circulating IgG-class autoantibodies in flight crew members was found. A symptom-free pilot was sampled before symptoms and then again afterward. This pilot developed clinical problems after flying for 45 h in 10 d. Significant increases in autoantibodies were noted to most of the tested proteins in the serum of this pilot after exposure to air emissions. The levels of autoantibodies rose with worsening of his condition compared to the serum sample collected prior to exposure. After cessation of flying for a year, this pilot's clinical condition improved, and eventually he recovered and his serum autoantibodies against nervous system proteins decreased. The case study with this pilot demonstrates a temporal relationship between exposure to air emissions, clinical condition, and level of serum autoantibodies to nervous system-specific proteins. Overall, these results suggest the possible development of neuronal injury and gliosis in flight crew members anecdotally exposed to cabin air emissions containing organophosphates. Thus, increased circulating serum autoantibodies resulting from neuronal damage may be used as biomarkers for chemical-induced CNS injury. The authors thank all of the participants who volunteered to take part in this case study. The technical work of Dr. Hagir B. Suliman and the art work of Sheref M. Abou-Donia are appreciated. This study was supported in part by the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.

Neuroprotective Effects by Nimodipine Treatment in the Experimental Global Ischemic Rat Model : Real Time Estimation of Glutamate

Glutamate is a key excitatory neurotransmitter in the brain, and its excessive release plays a key role in the development of neuronal injury. In order to define the effect of nimodipine on glutamate release, we monitored extracellular glutamate release in real-time in a global ischemia rat model with eleven vessel occlusion. TWELVE RATS WERE RANDOMLY DIVIDED INTO TWO GROUPS: the ischemia group and the nimodipine treatment group. The changes of extracellular glutamate level were measured using microdialysis amperometric biosensor, in coincident with cerebral blood flow (CBF) and electroencephalogram. Nimodipine (0.025 µg/100 gm/min) was infused into lateral to the CBF probe, during the ischemic period. Also, we performed Nissl staining method to assess the neuroprotective effect of nimodipine. During the ischemic period, the mean maximum change in glutamate concentration was 133.22±2.57 µM in the ischemia group and 75.42±4.22 µM (p<0.001) in the group treated with nimodipine. The total amount of glutamate released was significantly different (p<0.001) between groups during the ischemic period. The %cell viability in hippocampus was 47.50±5.64 (p<0.005) in ischemia group, compared with sham group. But, the %cell viability in nimodipine treatment group was 95.46±6.60 in hippocampus (p<0.005). From the real-time monitoring and Nissl staining results, we suggest that the nimodipine treatment is responsible for the protection of the neuronal cell death through the suppression of extracellular glutamate release in the 11-VO global ischemia model of rat.

Clindamycin is neuroprotective in experimental Streptococcus pneumoniae meningitis compared with ceftriaxone

In animal models of Streptococcus pneumoniae meningitis, rifampin is neuroprotective in comparison to ceftriaxone. So far it is not clear whether this can be generalized for other protein synthesis-inhibiting antimicrobial agents. We examined the effects of the bactericidal protein synthesis-inhibiting clindamycin (n = 12) on the release of proinflammatory bacterial components, the formation of neurotoxic compounds and neuronal injury compared with the standard therapy with ceftriaxone (n = 12) in a rabbit model of pneumococcal meningitis. Analysis of the CSF and histological evaluation were combined with microdialysis from the hippocampal formation and the neocortex. Compared with ceftriaxone, clindamycin reduced the release of lipoteichoic acids from the bacteria (p = 0.004) into the CSF and the CSF leucocyte count (p = 0.011). This led to lower extracellular concentrations of hydroxyl radicals (p = 0.034) and glutamate (p = 0.016) in the hippocampal formation and a subsequent reduction of extracellular glycerol levels (p = 0.018) and neuronal apoptosis in the dentate gyrus (p = 0.008). The present data document beneficial effects of clindamycin compared with ceftriaxone on various parameters linked with the pathophysiology of pneumococcal meningitis and development of neuronal injury. This study suggests neuroprotection to be a group effect of bactericidal protein synthesis-inhibiting antimicrobial agents compared with the standard therapy with beta-lactam antibiotics in meningitis.

Evaluation of plasma endothelin-1 levels in patients with cerebral infarction.

Endothelin-1 (ET-1) is a vasoconstrictor peptide derived from endothelium. Many authors have shown that ischemic stroke is associated with elevated plasma ET-1 levels. Also, the present findings related to plasma ET-1 levels with clinical status, size of the infarction, location of the infarction, and prognosis of the cerebral infarction were contradictory. In this study, plasma ET-1 levels in 30 patients with cerebral infarction within 72 hours after the onset of focal neurologic deficit and at their seventh day postinfarction were measured by a microplate enzyme immunoassay. Thirty sex- and age-matched healthy subjects were accepted as a control group. The mean plasma ET-1 concentrations in patients on admission, in patients at day 7, and in control subjects were 1.93 +/- 1.79, 1.03 +/- 1.02, and 0.65 +/- 0.32 fmol/mL, respectively. The mean plasma ET-1 level of patients on admission was found to be significantly higher than in patients at day 7 and in control subjects (p < 0.05). No significant difference in ET-1 levels was observed between the patients at day 7 and control subjects. Furthermore, there was no correlation between plasma ET-1 concentration and size of infarction, location of infarction, degree of clinical neurologic deficit, or prognosis of cerebral infarction. It was concluded that plasma ET-1 levels shortly after ischemic stroke were increased, which may be associated with the acute-phase reaction of cerebral infarction and may have deleterious effects on development of neuronal injury.

Neuronal recovery after moderate hypoxia is improved by the calpain inhibitor MDL28170

The role of calcium-activated proteolysis in hypoxic neuronal injury was investigated using an in vitro slice model of moderate hypoxia that mimics many features of an ischemic penumbra. The calpain inhibitor, MDL28170, significantly improved the recovery of synaptic responses in hippocampal slices following prolonged, moderate hypoxia without hypoxic depolarization. This finding further implicates calpain-mediated proteolysis in the development of neuronal injury following moderate metabolic challenge such as occurs in regions of partial ischemia.

Effect of L-arginine and NG-nitro-L-arginine on delayed neuronal death in the gerbil hippocampus

To assess the role of nitric oxide (NO) in cerebral ischemia, we investigated the effect of L-arginine, a substrate of NO synthase (NOS), and NG-nitro-L-arginine (L-NNA), a NOS inhibitorl on neuronal death in the CA1 hippocampal region. Seventy-two Mongolian gerbils were used in the study. Both carotid arteries were occluded for 4 min to induce forebrain ischemia. Temporal muscle temperature was strictly maintained at 37.5±0.3°C during the ischemia. L-arginine (70 and 100 mg kg-1) or L-NNA (11 10 and 100 mg kg-1) was administered intraperitoneally 4 times: 30 min beforel 3h, 6h and 24h after induction of ischemia. Four days after ischemic insultl the animals were perfusion-fixed, and the neuronal densities in the media, middle and lateral CA1 subfield were estimated. A verage neuronal cell density of the control group was 2-3 mm in each subfield. L-arginine at doses of 10 and 100 mg kg-1 did not prevent neuronal death. L-NNA at doses of 1 and 10 mg kg-1 did not protect neuronal cells from ischemia either. Howeverl in ischemia gerbils treated with 100 mg kg-1 L-NNAI the average neuronal cell density in the lateral CA 1 subfield was 54.4± 19.1. L-NNA (100 mg kg-1) significantly (p< O. 05) reduced the occurrence of neuronal death in the lateral CA1 subfield. The present results suggest that NO plays an important role in the development of neuronal injury after global ischemia. [Neural Res 1997; 19: 426-430]

The phospholipase A 2 inhibitor, quinacrine, reduces infarct size in rats after transient middle cerebral artery occlusion

The present study was conducted to evaluate the role of phospholipases in neuronal injury after transient focal ischemia. The phospholipase A 2 (PLA 2) inhibitor, quinacrine (5 mg/kg) or saline (of equal volume), was administered upon reperfusion to rats that underwent 2 h of middle cerebral artery occlusion (MCAO) via the intraluminal filament method. Rats were graded for neurological deficits based on a scale of 0–4, where 0 indicates no visible neurological deficits and 4 indicates most severe neurological deficits. After 2 h of focal ischemia, both groups of rats showed similar degrees of stroke, receiving median scores of 4. However, after 24 h of reperfusion the quinacrine treated rats ( n = 18) showed significantly lower deficit scores compared to the saline controls ( n = 15). Median scores were 1 and 3 and mean ranks were 12.28 and 23.14, respectively ( P < 0.01, Mann-Whitney U-test). Moreover, this effect of quinacrine persisted for up to 7 days when the quinacrine treated rats continued to receive a median score of 1, whereas the saline treated rats received a median score of 2. The mean ranks were significantly lower in the quinacrine group (14.68) compared to the saline controls (21.54) ( P < 0.05). After the last neurological test was conducted, the rats were sacrificed and their brains embedded in paraffin for histopathologicaal analysis. Quinacrine treated rats showed significantly reduced infarct areas in the caudoputamen compared to saline treated rats ( P < 0.05, Student's t-test). When both cortical and striatal damage were summed, quinacrine treated animals also exhibited a significantly lower degree of damage compared to saline controls ( P < 0.05). This study supports the notion that PLA 2 plays an important role in the development of neuronal injury following transient focal ischemia.

Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes

Formation of reactive oxygen species and disfunction of the excitatory amino acid (EAA) system are thought to be key events in the development of neuronal injury in several acute and long-term neurodegenerative diseases. Recent evidence suggests that the two phenomena may be interdependent. The present study is aimed at exploring possible molecular mechanisms underlying oxygen radical-EAA interaction. Exposure of cortical astrocytic cultures to either xanthine + xanthine oxidase (X/XO), a free radical-generating system, or hydrogen peroxide (H2O2) results in a marked decrease of high-affinity glutamate transport. Within 10 min of X/XO application, uptake falls to approximately 60% of its control value. In parallel no detectable release of lactate dehydrogenase occurs. X/XO effect is abolished in the presence of a mixture of scavenger enzymes (superoxide dismutase+catalase) or by the disulfide-reducing agents glutathione and dithiothreitol (DTT), but not by lipophilic antioxidants or ascorbate. The time course of inhibition shows an almost linear decline of glutamate transport during cell exposure to free radicals, while upon their inactivation the decline stops but established inhibition persists for at least 1 hr. In this situation, application of DTT significantly restores transport function. These data suggest that free radicals inhibit glutamate uptake primarily by long-lasting oxidation of protein sulfhydryl (SH) groups. Chemical modifiers of free SH groups, such as p-chloromercuribenzoate and N-ethylmaleimide, also induce uptake inhibition. Na+/K+ ATPase is a known target of oxygen radicals and may be involved in glutamate uptake inhibition. Indeed, ouabain, a blocker of the pump, reduces uptake in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial meningitis in children: pathophysiology and treatment.

Recent studies of the pathophysiology of bacterial meningitis have suggested that the development of neuronal injury is related to the release of vasoactive substances or alteration of blood-brain barrier permeability. Cerebral edema, increased intracranial pressure (ICP), systemic hypotension, decreased cerebral perfusion pressure, vascular inflammation, thrombosis, and a variety of other vascular changes may result in global or regional reductions in cerebral blood flow (CBF), which contribute to this insult. Approximately one-third of infants and children with bacterial meningitis will have markedly reduced CBF, and even in those children with normal total flow, regional hypoperfusion is common. Reduced CBF is associated with cerebral edema and a poor prognosis. A poor prognosis also is associated with reduced cerebral perfusion pressure. This occurs early in the course of meningitis and is primarily due to increased ICP rather than systemic hypotension. Autoregulation is preserved, suggesting that local ischemic tissue injury is more related to factors such as regional edema formation, focal vascular pathology, or specific intrinsic flow/metabolic abnormalities than to a reduction in systemic blood pressure. In contrast with other acute CNS insults, CBF/PCO2 reactivity is well preserved in many patients with meningitis; this raises the possibility that hyperventilation may cause further ischemic injury in those patients with marginal CBF. Although it is still unclear that treatment of increased ICP will affect outcome, we propose a treatment paradigm based on the results of neuroimaging studies and ICP measurements.