The effects of ageing on the activity of copper-zinc superoxide dismutase (SOD), selenium-dependent and independent glutathione peroxidase (GSH-Px) and catalase in several areas of the brain in 3-, ...12-, and 24-month-old rats were studied. In addition, the effects of a subacute intracerebroventricular treatment of NGF (1 microgram daily for 28 consecutive days) on SOD, GSH-Px, and catalase activity in the same areas of the brain were assessed. The effects of ageing on the activities of antioxidant enzymes varied considerably in the different brain areas studied. Copper-zinc SOD was alone in being unaffected by ageing. Intraventricular infusion of NGF significantly increased SOD activity in the prefrontal cortex, hypothalamus, caudate nucleus, and mesencephalon of 24-month-old rats. Selenium-dependent GSH-Px activity did not significantly change in 12-month-old rats but it increased in the lower brain stem of 24-month-old animals. In comparison to vehicle-treated rats, NGF significantly increased selenium-dependent GSH-Px activity in all brain areas studied in 12- and 24-month-old rats. Catalase activity decreased significantly in the majority of the brain areas studied in 12- and 24-month-old rats. NGF completely restored the fall in catalase activity in 12- and 24-month-old animals to levels similar to those occurring in young rats. In conclusion, the present experiments show, for the first time, that long-term intraventricular administration of NGF significantly increases in old animals the activity of key enzymes involved in the metabolic degradation of superoxide radicals and hydrogen peroxide.
The effect of IL-1β and TNFα infused into nucleus tractus solitari (NTS), nucleus parabrachialis medialis (NPBmed) and third cerebral ventricle of normotensive rats on blood pressure (BP) and heart ...rate (HR) was investigated.Microinfusion of IL-1β and TNFα into the third cerebral ventricle and NPBmed of normotensive rats produced a dose-dependent hypotensive and bradycardic response. A similar cardiovascular response was produced by infusion of IL1β into NTS but not by TNFα.When rats were pre-treated with
Escherichia coli lipopolisaccharide (LPS), an enhancement of cardiovascular response elicited by IL-1β and TNFα was found. Thus, IL-1β and TNFα produce cardiovascular responses when infused into specific areas of the CNS. This effect is potentiated by LPS and this may explain the alteration in cardiovascular regulation which can be observed in diseases in which an excess of circulating endotoxins and cytokines may occur.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The discovery of potential antiseizure drugs (ASDs) requires the use of experimental models that can also provide a unique chance for identifying new effective molecules able to prevent and/or cure ...epilepsy. Most of the preclinical knowledge on epileptogenesis derives from studies performed on post-insult models that are characterized by a recognizable first insult, a silent period lasting until the onset of the first seizure and a chronic period characterized by spontaneous recurrent seizures (SRSs). At odds, genetic models, in which the first insult remains to be identified, have been poorly investigated. Among the genetic models, the WAG/Rij rat was validated as a suitable experimental model of absence epileptogenesis with neuropsychiatric symptomatology, in which, according to our previous hypothesis on SRSs onset, genes could be considered the first ‘insult’ underlying all plastic modifications supporting the occurrences of absence seizures in this strain. In fact, in several genetic models, the initial insult could be described as the mutation leading to epilepsy that, to date, remains to be defined in this strain. The silent period ends at the occurrence of the first SRS, which is approximately at 2-3 months of age in these rats and after that time the chronic phase initiates, in which, absence seizures increase over time underlying likely further epileptogenic processes. In this review, we describe both the features of this experimental model and the effects of several pharmacological treatments against epileptogenesis and its related comorbidities including depressive-like symptoms and cognitive decline.
Nitric oxide may influence pathophysiology of brain ischemia in a complex way depending on the sources of its production either from neurons or endothelial cells. We investigated whether inhibition ...of nitric oxide synthesis affects postischemic neuronal death in hippocampus. Moreover, we evaluated whether the presence of nitric oxide synthase activity in specific neurons protects these against ischemia in the hippocampus, striatum, and sensorimotor cortex.
To inhibit nitric oxide synthase, several dosing regimens of NG-nitro-L-arginine methyl ester (L-NAME) were used (5 or 50 mg/kg IP, twice a day for 4 days, or 30 mg/kg IV) in gerbils. Control animals received either the isomer NG-nitro-D-arginine methyl ester or the vehicle. The gerbils underwent 10-minute occlusion of carotid arteries under ether anesthesia and controlled body temperature while physiological parameters were monitored. Neuronal damage was assessed 5 days after ischemia using Nissl-stained sections of hippocampus. Nitric oxide synthase neurons were histochemically stained for reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity.
L-NAME treatments, but not the chronic one at 5 mg/kg, induced elevation of blood pressure (30% to 80% greater than the control level, P < .01), as observed shortly before and after bilateral carotid occlusion. Postischemic neuronal loss in the CA1 through CA4 sectors was worsened by chronic pretreatment with L-NAME at 50 mg/kg (eg, CA1 neuronal counts per 100-microns length: 3.2 +/- 2.74, mean +/- SD; n = 19; P < .01). After the acute (30 mg/kg) or chronic pretreatment at lower dosage (5 mg/kg) with L-NAME, neuronal loss was comparable to that of animals treated with the D-isomer or the vehicle (CA1 counts in vehicle-treated animals: 7.65 +/- 6.51, mean +/- SD; n = 14). None of the L-NAME treatments affected postischemic survival of NADPH diaphorase-positive neurons in hippocampus, striatum, and sensorimotor cortex.
These observations demonstrate that inhibition of endothelial and neuronal nitric oxide synthase activity does not modify resistance of nitric oxide-producing neurons to transient ischemia. The severe inhibition of nitric oxide production aggravates postischemic neuronal death in the hippocampus, whereas the mild inhibition is ineffective.
Overproduction of free radical species has been shown to occur in brain tissues after ischemia-reperfusion injury. However, most of free radical scavengers known to antagonize oxidative damage (e.g. ...superoxide dismutase, catalase), are unable to protect against ischemia-reperfusion brain injury when given in vivo, an effect mainly due to their difficulty to gain access to brain tissues. Here we studied the effect of a low molecular weight superoxide dismutase mimetic (M40401) in brain damage subsequent to ischemia-reperfusion injury in Mongolian gerbils.
In animals undergoing ischemia-reperfusion injury, neuropathological and ultrastructural changes were monitored for 1-7 days either in the presence or in the absence of M40401 after bilateral common carotid artery occlusion (BCCO). Administration of M40401 (1-40 mg/kg, given i.p. 1 h after BCCO) protected against post-ischemic, ultrastructural and neuropathological changes occurring within the hippocampal CA1 area. The protective effect of M40401 was associated with a significant reduction of the levels of malondialdehyde (MDA; a marker of lipid peroxidation) in ischemic brain tissues after ischemia-reperfusion.
Taken together, these results demonstrate that M40401 provides protective effects when given early after the induction of ischemia-reperfusion of brain tissues and suggest the possible use of such compounds in the treatment of neurological dysfunction subsequent to cerebral flow disturbances.
The aim of this study was to assess the effects of dexamethasone (DEX) on the inducible bioconversion of glyceryl trinitrate (GTN) into nitric oxide in cultured smooth muscle cells, endothelial ...cells, and the J774 macrophage cell line as well as in vivo and ex vivo in rats either untreated or pretreated with Escherichia coli lipopolysaccharide. In vitro, an increased bioconversion of GTN to nitrite and an elevation of cyclosine guanosine 3,5´-monophosphate (cGMP) levels occurred after treatment with lipopolysaccharide (LPS) (0.5 μg/ml, 18 h). This effect was ablated by co-incubation with DEX (10 μM, 18 h). Rats treated with an intraperitoneal (IP) injection of LPS (4 mg/kg) 18 h beforehand showed enhanced hypotensive responses to GTN (1 mg/kg, intravenously IV) and this was prevented when DEX (4 mg/kg, IP) was given together with LPS. Progesterone (50 mg/kg, IP) had no effect on GTN–induced hypotensive response. Conversely, exposure of rat aortic strips obtained from animals pretreated with LPS produced an enhanced vasorelaxant response in LPS-treated rats. Also, this effect was inhibited by pretreatment with DEX. Thus, the induction of the pathway leading to the formation of nitric oxide from GTN is blocked by DEX both in vitro and in vivo, and this may represent a useful tool in the assessment of the enhanced bioconversion of organic nitrates into nitric oxide occurring via inflammatory mechanisms.
The effects of tacrine (5 mg/kg i.p.), a potent acetylcholinesterase inhibitor, were studied in rats pretreated (24 h beforehand) with a single dose (12 mEq/kg i.p.) of LiCl. Tacrine and LiCl were ...ineffective when given individually. Tacrine elicited seizures and brain damage in 90% of the rats treated. The intracerebroventricular microinfusion of N omega-nitro-L-arginine methyl ester (300 micrograms given 24 h after LiCl administration) significantly reduced the seizures and brain damage produced by tacrine (given 15 min later). These experiments suggest that the seizures and brain damage elicited by tacrine may be due, in part, to increased nitric oxide production in the brain.
The gross behavioural, electrocortical and neuropathological effects of kainate (10mg/kg i.p,) and ouabain (1μg, given into one dorsal hippocampus) were studied in rats. The effects of these ...treatments on nitric oxide synthase (NOS) activity in homogenates of hippocampus and cortex were also studied. Administration of kainate or ouabain produced motor and electrocortical seizures similar for latency to onset (approximately 15min) and intensity (in all instances 80–100% of the treated rats showed behavioural and electrographic seizures). These effects were accompanied at 24 h by severe damage to all subsectors of the hippocampal formation and this concerned a similar proportion of the treated rats (n=4–8 per treatment). No significant changes in nitric oxide synthase (NOS) activity were noted in the cerebral cortex and hippocampus of rats receiving injections of kainate and ouabain. In addition, pretreatment with Nω-Nitro-L-arginine methyl ester (300μg, given into one lateral cerebral ventricle 15 min previously) was ineffective in preventing the effects of kainate and ouabain. In conclusion, present data suggest that excessive production of NO is not involved in the mechanisms triggering seizures and neurodegeneration produced by kainate or ouabain.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The activity of catalase, the main enzyme responsible for detoxification against hydrogen peroxide, decreases in specific brain areas of aged rats. The reduction of enzyme activity appears to be the ...consequence of a decreased protein expression rather than an impaired function of the native enzyme. In fact, diminution of the immunoreactive protein parallels enzyme activity decrease. Since the extent of decrease of both activity and protein content was observed to be area dependent, we hypothesise that this phenomenon may underlie, at least in part, the increased susceptibility of specific brain regions to oxidative insults observed in pathological situations related to ageing.
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