Brain Damage In Mice Research Articles

Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins.

Previously we found that some cyclopentenone prostaglandin derivatives promoted neurite outgrowth from PC12 cells and dorsal root ganglia explants in the presence of nerve growth factor; and so we referred to them as neurite outgrowth-promoting prostaglandins (NEPPs). In this study, NEPPs protected HT22 cells against oxidative glutamate toxicity. NEPP6, one of the most effective promoters of neurite outgrowth in PC12 cells, protected the cells most potently among NEPPs 1--10. Several derivatives, NEPPs 11--19, were newly synthesized based on the chemical structure of NEPP6. NEPP11 had a more potent neuroprotective effect than NEPP6. NEPP11 also prevented the death of cortical neurons induced by various stimuli and reduced ischemic brain damage in mice. Biotinylated compounds of NEPPs were synthesized to investigate their cellular accumulation. NEPP6-biotin protected the cells and emitted potent signals from the cells. In contrast, biotinylated non-neuroprotective derivatives emitted much weaker signals. These results suggest that NEPPs are novel types of neurotrophic compounds characterized by their dual biological activities of promoting neurite outgrowth and preventing neuronal death and that their accumulation in the cells is closely associated with their neuroprotective actions.

Neurotrophic actions of novel compounds designed from cyclopentenone prostaglandins

Previously we found that some cyclopentenone prostaglandin derivatives promoted neurite outgrowth from PC12 cells and dorsal root ganglia explants in the presence of nerve growth factor; and so we referred to them as neurite outgrowth‐promoting prostaglandins (NEPPs). In this study, NEPPs protected HT22 cells against oxidative glutamate toxicity. NEPP6, one of the most effective promoters of neurite outgrowth in PC12 cells, protected the cells most potently among NEPPs 1–10. Several derivatives, NEPPs 11–19, were newly synthesized based on the chemical structure of NEPP6. NEPP11 had a more potent neuroprotective effect than NEPP6. NEPP11 also prevented the death of cortical neurons induced by various stimuli and reduced ischemic brain damage in mice. Biotinylated compounds of NEPPs were synthesized to investigate their cellular accumulation. NEPP6‐biotin protected the cells and emitted potent signals from the cells. In contrast, biotinylated non‐neuroprotective derivatives emitted much weaker signals. These results suggest that NEPPs are novel types of neurotrophic compounds characterized by their dual biological activities of promoting neurite outgrowth and preventing neuronal death and that their accumulation in the cells is closely associated with their neuroprotective actions.

Protective effect of harmalol and harmaline on MPTP neurotoxicity in the mouse and dopamine-induced damage of brain mitochondria and PC12 cells.

The present study elucidated the protective effect of beta-carbolines (harmaline, harmalol, and harmine) on oxidative neuronal damage. MPTP treatment increased activities of total superoxide dismutase, catalase, and glutathione peroxidase and levels of malondialdehyde and carbonyls in the basal ganglia, diencephalon plus midbrain of brain compared with control mouse brain. Coadministration of harmalol (48 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. Harmaline, harmalol, and harmine attenuated both the 500 microM MPP(+)-induced inhibition of electron flow and membrane potential formation and the 100 microM dopamine-induced thiol oxidation and carbonyl formation in mitochondria. The scavenging action of beta-carbolines on hydroxyl radicals was represented by inhibition of 2-deoxy-D-ribose degradation. Harmaline and harmalol (100 microM) attenuated 200 microM dopamine-induced viability loss in PC12 cells. The beta-carbolines (50 microM) attenuated 50 microM dopamine-induced apoptosis in PC12 cells. The compounds alone did not exhibit significant cytotoxic effects. The results indicate that beta-carbolines attenuate brain damage in mice treated with MPTP and MPP(+)-induced mitochondrial damage. The compounds may prevent dopamine-induced mitochondrial damage and PC12 cell death through a scavenging action on reactive oxygen species and inhibition of monoamine oxidase and thiol oxidation.

Ischemic Brain Damage in Mice after Selectively Modifying BDNF or NT4 Gene Expression

The neurotrophins and the tyrosine kinase (Trk) B receptor may play a protective role in the pathophysiology of cerebral ischemia. In this study, the authors investigated whether reducing endogenous expression of TrkB-binding neurotrophins modifies the susceptibility to ischemic injury after 1-hour middle cerebral artery occlusion followed by 23 hours of reperfusion in a filament middle cerebral artery occlusion model. Mice lacking both alleles for neurotrophin-4 (nt4-/-) or deficient in a single allele for brain-derived neurotrophic factor (bdnf+/-) exhibited larger cerebral infarcts compared to wild-type inbred 129/SVjae mice (68% and 91%, respectively, compared to controls). Moreover, lesions were larger (21%) in nt4-/- mice after permanent middle cerebral artery occlusion. Hence, expression of both NT4 and BDNF, and by inference the TrkB receptor, confers resistance to ischemic injury.

Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice.

In this investigation, 40 mg/kg of the excitatory neurotoxin kainic acid (KA) was subcutaneously administered to CD2-F1 mice. In this mouse strain morphological damage induced by KA in the hippocampus was markedly concentrated in the CA3 pyramidal neurons. Neuronal injury was accompanied by several pathological neurobehavioral activities including arching of tail, tremors and seizures, and by certain biochemical changes, i.e., increased lipid peroxidation products (LPO) in the brain. When melatonin was injected intraperitoneally at a single dose of 5 mg/kg 10 min before KA administration, it significantly reduced these pathological neurobehavioral changes and almost completely attenuated the increase in LPO and morphological damage induced by KA. The neuroprotective effect of melatonin against KA-induced brain damage in mice is believed to be in part related to its oxygen radical scavenging properties as well as its antiepileptic and GABA receptor regulatory actions. Considering melatonin's relative lack of toxicity and ability to enter the brain, these results along with previous evidence suggest that melatonin, which is a natural substance, may be useful in combating free radical-induced neuronal injury in acute situations such as stroke and brain trauma as well as neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease that have free radicals as causative factors.

A novel lipophilic spin probe for the measurement of radiation damage in mouse brain using in vivo electron spin resonance (ESR)

As a possible lipophilic spin probe of in vivo electron spin resonance (ESR), 3-methoxy carbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-yloxy (MCPROXYL) was examined. The permeability of the blood-brain barrier to this compound was evaluated with a brain uptake index and autoradiography, with result that this probe is well distributed in the brain. The in vivo ESR spectra were measured in the head and the abdomen of MCPROXYL-injected living mice. The rate of signal decay of MCPROXYL in the head measured at one hour after X-irradiation was about 75% of that of the controls. The decrease in the head seems to be related to the early response of the brain to X-irradiation. This is the first report that the behavior of free radical such as MCPROXYL in the brain is influenced by X-irradiation. MCPROXYL is thus useful as a novel spin probe for in vivo ESR to monitor the radiation damage in the brain.

Modelling the effects of age-related mtDNA mutation accumulation; Complex I deficiency, superoxide and cell death

Deleterious mitochondrial mutations accumulate during normal human aging in postmitotic tissues. How these mutations affect aging cells is currently unknown. This issue has been addressed in two ways. The first is to determine the likeliest effect of random mutations in the mitochondrial genome, and of the 4977 bp deletion and MELAS point mutation that rise in frequency with age. The results indicate that Complex I is statistically much more likely to be affected than any other product of the mitochondrial genome. We have also attempted to model Complex I deficiency in animals with the drug MPTP, a specific inhibitor of Complex I. We find that MPTP causes massive damage in brains of mice with a genetic deficiency in the mitochondrial superoxide dismutase, MnSOD, but less in mice that overexpress the enzyme. We conclude from these data that MPTP-induced cell death must be mediated through an increase in the steady-state concentration of superoxide anion in mitochondria. Since the likeliest target of mitochondrial mutation is Complex I, deficiency of which causes MnSOD-inhibitable lethality, we propose that rising mtDNA mutations with age will cause an increase in superoxide-mediated cell death. Such a mechanism for age-related cell death has the potential to explain several age-related phenotypes.

An in vitro model of anoxic-induced damage in mouse brain.

An in vitro model of anoxic-induced brain damage was developed to help elucidate the biochemical basis of cell damage due to reduced oxygen availability. Mouse forebrain slices were preincubated under various conditions (treatment incubation). The effects of this treatment incubation on [14C]acetylcholine (ACh) and 14CO2 production from [U-14C]glucose were subsequently assessed in an incubation under optimal conditions (test incubation). A variety of treatment incubation conditions decreased 14CO2 and 14C-ACh production in the test incubation in parallel (r = 0.932). For example, treatment incubations with no oxygen and high K+ reduced test incubation ACh (-63.2%) and CO2 (-67.3%) production. An anoxic-induced increase in calcium-45 uptake and the amelioration of anoxic induced changes by the calcium antagonist verapamil or by the omission of calcium from the treatment incubation suggest that altered calcium homeostasis was important in the production of the anoxic-induced deficits. These results provide in vitro evidence that anoxic induced increases in calcium may be pathophysiologically important and that reducing calcium entry postsynaptically may alleviate anoxic-induced changes. This model may prove useful in elucidating the molecular basis of these changes.

Seizures produced by pilocarpine in mice: A behavioral, electroencephalographic and morphological analysis

Increasing doses of pilocarpine, 100–400 mg/kg, were given intraperitoneally to mice and the resulting behavioral, electroencephalographic and neuropathological alterations were studied. No behavioral phenomena were observed in mice treated with the lowest dose of pilocarpine. Occasional tremor and myoclonus of hindlimbs were found in animals which received pilocarpine in a dose of 200 mg/kg. At doses of 300, 325 and 350 mg/kg, pilocarpine produced a sequence of behavioral alterations including staring spells, limbic gustatory automatisms and motor limbic seizures that developed over 15–30 min and built up progressively into a limbic status epilepticus lasting for several hours. The highest dose of pilocarpine, 400 mg/kg, was generally lethal to mice. Pilocarpine produced both interictal and ictal epileptiform activity in the electroencephalogram (EEG). The earliest EEG alterations appeared in the hippocampus and then spread to cortical areas. EEG seizures started 10–15 min after injection of large doses of pilocarpine, 300–350 mg/kg. Ictal periods lasted for 1–2 min, recurred every 5–10 min and were followed by periods of depression of the EEG activity. By 30–45 min paroxysmal activity resulted in a status epilepticus. Examination of frontal forebrain sections with light microscopy revealed a widespread damage to several brain regions including the hippocampus, amygdala, thalamus, olfactory cortex, neocortex and substantia nigra. Scopolamine, 10 mg/kg, and diazepam, 10 mg/kg, prevented the development of convulsive activity and brain damage produced by pilocarpine. The results emphasize that excessive and sustained stimulation of cholinergic receptors can lead to seizures and seizure-related brain damage in mice. It is proposed that systemic pilocarpine in mice provides a useful animal model for studying mechanisms of and therapeutic approaches to temporal lobe epilepsy.

Localization of brain damage in mice following Toxoplasma infection.

(1984). Localization of brain damage in mice following Toxoplasma infection. Annals of Tropical Medicine & Parasitology: Vol. 78, No. 6, pp. 657-659.

Protective effect of mono- and disaccharides on glutamate-induced brain damage in mice

The effect of materials administered simultaneously with monosodium l-glutamate (MSG) was studied in 10-day-old mice to assess the histological brain lesion. By gavage, sodium chloride did not promote glutamate-induced brain damage, while the mono- and disaccharides glucose, fructose, galactose, sucrose and lactose significantly reduced the number of necrotic neurons in the arcuate nucleus (AN) of the hypothalamus.

Amnesia following cortical brain damage in mice

Mice were subjected to either bilateral frontal pole, anterior-medial, posterior-medial or occipital cortical brain damage one day before or immediately after training in a one-trial passive avoidance task. Both pretrial and posttrial frontal lesions and both pretrial and posttrial anterior-medial lesions impaired retention 24 hr after training; posterior-medial and occipital lesions had no significant effects at any time. Anterior-medial lesions impaired retention when surgery was performed as long as 8 hr after training; frontal lesions impaired retention only when surgery was performed within the first post-trial hour. When retest was conducted 1 hr after training and surgery was performed immediately after training, frontal lesions but not anterior-medial lesions impaired retention. The results indicated that the cortex participates in memory storage and furthermore that substrates for modulating long-term and short-term storage could be distinguished.

Comparative recovery following simultaneous- and successive-stage frontal brain damage in mice.

Comparative recovery following simultaneous- and successive-stage frontal brain damage in mice.

Recovery of function following frontal brain damage in mice: changes in sensitivity to amphetamine.

Recovery of function following frontal brain damage in mice: changes in sensitivity to amphetamine.

Relationships between chemical changes and histological damage in the brains of scrapie affected mice

An attempt has been made to correlate chemical changes with the degree and extent of histological damage in mouse brains infected with the “Suffolk strain” of scrapie. A scheme is described for the combined grading of degree of brain damage and distribution of lesions based on neuronal vacuolation and spongy degeneration. Considerable variation was found in the extent to which the mice were affected with scrapie. There was good correlation between change in body weight and histological grading and also a progressive decrease in brain weight with increase in extent of lesions. A slight decrease in mean density of brain tissue was observed. Total dry matter and protein concentrations remained constant. The sodium concentration remained constant, but there was 5 per cent. decrease in potassium concentration. A rise in acid proteinase activity appeared at the same time as minimal lesions, but reached a maximum before widespread lesions were present. There were no gross changes in the concentration of total free amino-acids. Since the total dry matter and protein concentrations alter very little, excess products of protein hydrolysis arising from increased acid proteinase activity must be removed rapidly from the brain. It is possible that the release of waste products may occur in sudden localised outbursts.