Transient cerebral ischemia induces, besides delayed neurodegeneration in selected brain structures, a number of early responses which may mediate ischemic injury/repair processes. Here we report that 5 min exposure to cerebral ischemia in gerbils induces a rapid inhibition and subsequent translocation of Ca (2+)/calmodulin-dependent protein kinase II (CaMKII). These changes were partially reversible during a 24 h post-ischemic recovery. Concomitantly the total amount of the enzyme protein, as revealed by Western blotting (alfa- -subunit specific), remained stable. This is consistent with our previous hypothesis, that the mechanism of ischemic CaMKII down-regulation involves a reversible posttranslational modification-(auto)phosphorylation, rather then the degradation of enzyme protein. The effectiveness of known modulators of postischemic outcome in counteracting CaMKII inhibition was tested. Three of these drugs, namely dizocilpine (MK-801), N-nitro-L-arginine methyl ester (L-NAME) and gingkolide (BN52021), all significantly attenuated the enzyme response to ischemia, whereas an obvious diversity in the time-course of their actions implicates different mechanisms involved.
Despite the numerous reports on the role of tumor necrosis factor-alpha (TNF-alpha) in the brain neuropathology, very little is known about the mechanisms by which TNF-alpha may mediate neuroprotection. Different hypotheses pertain to the molecular and cellular effectors triggered by the activation of TNF receptors (TNFRI and TNFR2). They are focused on diminishing the production of nitric oxide and free radicals, alteration of excitatory amino acids neurotransmission, maintenance of neuronal calcium homeostasis and induction of neurotrophic factors synthesis. In this review all these data are summarized. Moreover, possible explanations for the inconsistent data concerning the TNF-alpha effect on neuron are discussed.
Ginseng, the root of the Panax species, is a well-known herbal medicine. Traditionally it has been used in Korea, China and Japan for thousands of years. Nowadays it has become a popular and worldwide known health drug. Current scientific studies demonstrate in vivo and in vitro its beneficial effects in a wide range of pathological conditions such as cardiovascular disease, cancer, immune deficiency and hepatotoxicity. Ginsenosides or ginseng saponins as the active ingredients have antioxidant, anti-inflammatory, anti-apoptotic and immunostimulant properties, which raised speculations that these compounds could positively affect neurodegenerative disorders and delay neuronal aging. Conclusive clinical data in humans are still missing. However, results from animal studies and neuronal cell culture experiments indicate that ginsenosides can counteract and attenuate factors promoting neuronal death as environmental toxins, excitotoxic action of glutamate and rises in intracellular calcium, excessive release of free radicals and apoptotic events. Thus, neuroprotective actions of ginsenosides could come about as a valuable option to slow down neurodegenerative diseases.
Intermittent hypoxia stimulates the development of adaptive responses, called preconditioning. This process is partially mediated by genetic remodeling, via hypoxia inducible factor (HIF), which induces long-term adaptation processes and is responsible for the increase of levels of vascular endothelial growth factor (VEGF), erythropoietin (Epo), atrial natriuretic peptide (ANP), and nitric oxide (NO). The synthesis of brain-derived neurotrophic factor (BDNF) participates in the control of neural plasticity after hypoxia. The mechanisms of neuroprotection against hypoxia may be related to vascular adjustments and to central neurogenic neuroprotection. Some of the factors known to be involved in the development of the mechanism of neuroprotection are also present in the responses to repetitive apneas that occur during sleep in patients with obstructive sleep apnea (OSA) syndrome, who are frequently exposed to severe sleep hypoxemia. It appears that OSA syndrome represents a clinical example of preconditioning and the development of adaptive responses to intermittent hypoxia.
The pathological process of neurodegeneration is accompanied by an inflammatory reaction that is believed to contribute to the pathogenesis of neurodegenerative diseases. The aim of our study was to evaluate the influence of autoimmune reaction induced by post-traumatic vaccination with myelin self-antigen on spontaneous regeneration of dopaminergic neurons, injured with MPTP. C57BL mice were intoxicated with 40 mg/kg MPTP and seven days later immunized with MOG 35-55 peptide in CFA. On 7th day following intoxication, the MPTP treated mice showed decrease of dopamine level by 63% as compared to the control mice. However, starting from the 14th day following intoxication, a spectacular increase of dopamine content was observed. Immunization with MOG resulted in statistically significant reduction of the increase in striatum as compared to non-immunized animals, and was lower by 23%, 17% and 15% on days 14, 28 and 50, respectively. Our results show suppressive influence of autoimmune reaction induced after injury on regeneration of dopamine cells intoxicated with MPTP.
Carvedilol a beta-adrenoreceptor antagonist with potent antioxidant properties raises high expectations in therapy of ischemia. In this study the effect of carvedilol on neuronal survival after transient forebrain ischemia in gerbils was investigated. The role of poly(ADP-ribose) polymerase (PARP-1) in this process was evaluated. Our data indicated that carvedilol administered subcutaneously in a dose of 7 or 70 mg/kg b.w. directly after 5 min of transient forebrain ischemia protects significant population of neurons in hippocampal area CA1, but has no effect after induction of prolonged 10 min ischemia. Carvedilol significantly decreased PARP activity in hippocampus that was markedly increased after both 15 min and 4 days of reperfusion following 5 min of ischemia. Moreover, carvedilol prevented NAD+ depletion after ischemic-reperfusion insult. These results indicated that carvedilol protects neurons against death and suggested that suppression of PARP activity during reperfusion could be involved in this process.
To estimate protective potential of citicoline in a model of birth asphyxia, the drug was given to 7-day old rats subjected to permanent unilateral carotid artery occlusion and exposed for 65 min to a hypoxic gas mixture. Daily citicoline doses of 100 or 300 mg/kg, or vehicle, were injected intraperitoneally for 7 consecutive days beginning immediately after the end of the ischemic-hypoxic insult, and brain damage was assessed by gross morphology score and weight deficit two weeks after the insult. Caspase-3, alpha-fodrin, Bcl-2, and Hsp70 levels were assessed at 0, 1, and 24 h after the end of the hypoxic insult in another group of rat pups subjected to the same insult and given a single dose of 300 mg/kg of citicoline or the vehicle. Citicoline markedly reduced caspase-3 activation and Hsp70 expression 24 h after the insult, and dose-dependently attenuated brain damage. In the context of the well-known excellent safety profile of citicoline, these data suggest that clinical evaluation of the efficacy of the drug in human birth asphyxia may be warranted.
Elevated homocysteine is a risk factor in cardiovascular diseases and neurodegeneration. Among the putative mechanisms of homocysteine-evoked neurotoxicity, disturbances in methylation processes and NMDA receptor-mediated excitotoxicity have been suggested. Our previous studies demonstrated that group I metabotropic glutamate receptors along with NMDA receptors participate in acute homocysteine-induced neuronal damage. In this study, using propidium iodide staining, we tested whether the same mechanism may mediate chronic homocysteine neurotoxicity. Our results confirmed that the application of D,L-homocysteine in micromolar concentrations for 3 days induces neurodegeneration in primary cultures of cerebellar granule neurons. Uncompetitive NMDA receptor antagonist MK-801, and mGlu1 or mGlu5 receptor antagonists (LY367385 and MPEP, respectively), given alone provided very limited neuroprotection. However, simultaneous application of the NMDA receptor antagonists MK-801, memantine or amantadine and MPEP almost completely prevented chronic homocysteine neurotoxicity. These findings suggest a novel therapeutic strategy to combat neurodegeneration induced by hyperhomocysteinemia comprising a combination of antagonists of group I metabotropic glutamate receptors and NMDA receptors.
The finding of stem/progenitor cells in postnatal bone marrow and umbilical cord blood, opens up a possibility of using stem cells to treat neurologic diseases. There is a controversy, whether intravenously administered human umbilical cord blood cells (HUCBC) migrate to the brain, differentiate and improve recovery after ischemia. In this study, 1-3 ?10^6 cells from non-cultured (non-committed) mononuclear HUCBC fraction were intravenously infused 1, 2, 3 or 7 days after a transient middle cerebral artery occlusion (MCAo) in adult rats. We found few human cells only in the ischemic area, localized mostly around blood vessels with few positive cells in the brain parenchyma. Timing of HUCBC delivery after ischemia or injection of Cyclosporin A at the time of delivery, had no effect on the number of human cells detected in the ischemic brain. Infusion of HUCBC did not reduce infarct volume and did not improve neurologic deficits after MCAo, suggesting that HUCBC failed to migrate/survive in the ischemic brain and did not provide significant neurological benefits.
A focal cold lesion-induced injury, i.e., a model of focal vasogenic brain edema, enhances the permeability of the blood-brain barrier and cell membrane in the perilesional rim. However, non-intact cells can be detected, e.g. by markers of apoptosis, only hours or even days after the injury. The early membrane dysfunction allows extravasated serum proteins to enter the injured cells, which can be readily visualized if the plasma albumin was previously bound to fluorescent tracers, such as Evans Blue (EB). The aim of this study was to demonstrate injured cells that take up the EB/albumin conjugate in the perilesional rim. This tracer was administered 3.5 h after the induction of the injury and the animals were sacrificed 30 min later. With an excitation wavelength of 530-550 nm, the EB-positive cells emitted bright-red fluorescence at > 590 nm and were easy to count. No positive cells were observed in the controls. This method provides more information than the classical 2,3,5-triphenyltetrazolium chloride reaction, because it permits an assessment of the density and distribution of cells with non-intact cell membranes in the perilesional area following cerebrocortical injury.
Adaptive mechanisms may diminish the detrimental effects of recurrent nocturnal hypoxia in obstructive sleep apnea (OSA). The potential role of elevated carbon dioxide (CO2) in improving brain oxygenation in the patients with severe OSA syndrome is discussed. CO2 increases oxygen uptake by its influence on the regulation of alveolar ventilation and ventilation-perfusion matching, facilitates oxygen delivery to the tissues by changing the affinity of oxygen to hemoglobin, and increases cerebral blood flow by effects on arterial blood pressure and on cerebral vessels. Recent clinical studies show improved brain oxygenation when hypoxia is combined with hypercapnia. Anti-inflammatory and protective against organ injury properties of CO2 may also have therapeutic importance. These biological effects of hypercapnia may improve brain oxygenation under hypoxic conditions. This may be especially important in patients with severe OSA syndrome.
. Sustained exposure to glucocorticosteroids (GCs), adrenal hormones secreted during stress, can cause neural degeneration. This is particularly so in the hippocampus, a principal neural target site for GCs. The purpose of this research was an assessment of the neuroprotective effect of ACTH (4-9) in degenerative changes of hippocampal neurons induced by synthetic GC - dexamethasone. Experiments were conducted on male Albino-Swiss mice. We studied the morphology of neurons in the dorsal hippocampus in slides stained with cresyl violet. Immunocytochemical analysis was carried out with the use of monoclonal antibody anti-MAP2 in order to detect alterations in the the neuronal cytoskeleton. We also performed ultrastructural examinations of hippocampal neurons. Quantitative analysis of morphological changes was completed using a computer analyser of histological pictures. It was shown that dexamethasone administered in toxic doses evokes neuronal death in layer CA3 of the hippocampus. Results indicate that ACTH (4-9) shows protective effects in that model. Dexamethasone-induced damage to hippocampal pyramidal neurons (assessed by cell counts, immunocytochemical analysis of cytoskeletal alterations and ultrastructural studies) was significantly reduced in animals administered ACTH (4-9).
Lipoic acid is a prostetic group of H-protein of the glycine cleavage system and the dihydrolipoamide acyltransferases (E2) of the pyruvate, alpha-ketoglutarate and branched-chain alpha-keto acid dehydrogenase complexes. Lipoic acid and its reduced form, dihydrolipoic acid, reacts with oxygen reactive species. This paper reviews the beneficial effects in oxidative stress models or clinical conditions.
Nicotinamide is an important cofactor in many metabolic pathways and a known neuroprotective substance, while its methylated product, 1-methylnicotinamide, is a suspected neurotoxin. Homocysteine is a risk factor in Alzheimer's disease and neurodegeneration, causing inhibition of methylation processes and inducing excitotoxicity. In this study, using primary cultures of rat cerebellar granule cells and propidium iodide staining, we investigated the neurotoxicity of nicotinamide and 1-methylnicotinamide, and their neuroprotective potential in acute and sub-acute homocysteine neurotoxicity. Our results demonstrated that nicotinamide and 1-methylnicotinamide applied for 24 h to cultures at concentrations of up to 25 mM had no effect on neuronal viability. Moreover, nicotinamide at concentrations of 5?20 mM and 1-methylnicotinamide at 1?10 mM applied to cells 24 h before, and for 24 h after an acute 30 min application of 25 mM D,L homocysteine, reduced neuronal damage. 1-Methylnicotinamide at concentrations of 250 and 500 ?M showed neuroprotective activity during a sub-acute 24-h exposure to 2.5 mM D,L-homocysteine, while 5 and 25 mM nicotinamide also evoked neuroprotection. These findings do not support suggestions that 1-methylnicotinamide may act as an endogenous neurotoxic agent; rather, they indicate the neuroprotective ability of nicotinamide and 1-methylnicotinamide in homocysteine neurotoxicity. The exact mechanisms of this neuroprotection are unclear and require further investigation.
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