The systemic administration of a potent muscarinic agonist pilocarpine in rats promotes sequential behavioral and electrographic changes that can be divided into 3 distinct periods: (a) an acute period that built up progressively into a limbic status epilepticus and that lasts 24 h, (b) a silent period with a progressive normalization of EEG and behavior which varies from 4 to 44 days, and (c) a chronic period with spontaneous recurrent seizures (SRSs). The main features of the SRSs observed during the long-term period resemble those of human complex partial seizures and recurs 2-3 times per week per animal. Therefore, the pilocarpine model of epilepsy is a valuable tool not only to study the pathogenesis of temporal lobe epilepsy in human condition, but also to evaluate potential antiepileptogenic drugs. This review concentrates on data from pilocarpine model of epilepsy.
Rats subjected to structural brain damage induced by sustained convulsions triggered by systemic administration of pilocarpine (PILO) are a useful model for investigation of the mechanisms essential for seizure generation and spread in rodents. After PILO administration, three distinct phases are observed: (a) an acute period of 1-2 days' duration corresponding to a pattern of repetitive limbic seizures and status epilepticus; (b) a seizure-free (silent) period characterized by a progressive return to normal EEG and behavior of 4-44 days' duration; and (c) a period of spontaneous recurrent seizures (SRS) starting 5-45 days after PILO administration and lasting throughout the animal's life. PILO (320-350 mg/kg intraperitoneally, i.p.) was administered to rats, and the content of hippocampal monoamines and amino acids was measured in the acute, silent, and SRS periods by liquid chromatography. Norepinephrine (NE) level was decreased during all periods whereas dopamine (DA) content was increased. Serotonin (5-hydroxytryptamine, 5-HT) was increased only in the acute period. Utilization rate measurement of monoamines showed increased NE consumption and decreased DA consumption during all phases. 5-HT utilization rate was increased only in the acute period. Amino acid content showed a decrease in aspartate (ASP) and glutamate (GLU) concentrations associated with increased gamma-aminobutyric acid (GABA) level during the acute period. The silent phase was characterized by a decrease in glycine (GLY) and GABA levels and an increase in GLU concentration. The SRS period showed an increase in all amino acid concentrations. These findings show important neurochemical changes in the course of establishment of an epileptic focus after brain damage induced by status epilepticus triggered by pilocarpine.
There is a great deal of evidence showing the capacity of physical exercise to enhance cognitive function, reduce anxiety and depression, and protect the brain against neurodegenerative disorders. Although the effects of exercise are well documented in the mature brain, the influence of exercise in the developing brain has been poorly explored. Therefore, we investigated the morphological and functional hippocampal changes in adult rats submitted to daily treadmill exercise during the adolescent period. Male Wistar rats aged 21 postnatal days old (P21) were divided into two groups: exercise and control. Animals in the exercise group were submitted to daily exercise on the treadmill between P21 and P60. Running time and speed gradually increased over this period, reaching a maximum of 18 m/min for 60 min. After the aerobic exercise program (P60), histological and behavioral (water maze) analyses were performed. The results show that early-life exercise increased mossy fibers density and hippocampal expression of brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B, improved spatial learning and memory, and enhanced capacity to evoke spatial memories in later stages (when measured at P96). It is important to point out that while physical exercise induces hippocampal plasticity, degenerative effects could appear in undue conditions of physical or psychological stress. In this regard, we also showed that the exercise protocol used here did not induce inflammatory response and degenerating neurons in the hippocampal formation of developing rats. Our findings demonstrate that physical exercise during postnatal development results in positive changes for the hippocampal formation, both in structure and function.
Aging is often accompanied by cognitive decline, memory impairment and an increased susceptibility to neurodegenerative disorders. Most of these age-related alterations have been associated with deleterious processes such as changes in the expression of inflammatory cytokines. Indeed, higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines are found in the aged brain. This perturbation in pro- and anti-inflammatory balance can represent one of the mechanisms that contribute to age-associated neuronal dysfunction and brain vulnerability. We conducted an experimental study to investigate whether an aerobic exercise program could promote changes in inflammatory response in the brains of aged rats. To do so, we evaluated the levels of tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL1β), interleukin 6 (IL6) and interleukin 10 (IL10) in the hippocampal formation of 18 month old rats that underwent treadmill training over 10 consecutive days. Quantitative immunoassay analyses showed that the physical exercise increased anti-inflammatory cytokine levels IL10 in the hippocampal formation of aged rats, when compared to the control group. The hippocampal levels of pro-inflammatory cytokines IL1β, IL6 and TNFα were not statistically different between the groups. However, a significant reduction in IL1β/IL10, IL6/IL10 and TNFα/IL10 ratio was observed in the exercised group in relation to the control group. These findings indicate a favorable effect of physical exercise in the balance between hippocampal pro- and anti-inflammatory during aging, as well as reinforce the potential therapeutic of exercise in reducing the risk of neuroinflammation-linked disorders.
Chronic migraine (CM) has been associated with idiopathic intracranial hypertension without papilloedema (IIHWOP), a significant percentage of these cases occurring in obese patients with intractable headache. A prospective study from February 2005 to June 2006 was made of 62 CM patients who fulfilled International Headache Society diagnostic criteria and had cerebral magnetic resonance venography (MRV) and lumbar puncture (LP) done. Two patients were excluded, six (10%) with elevated cerebrospinal fluid (CSF) open pressure (OP), five with body mass index (BMI) > 25. None of the patients had papilloedema or abnormal MRV. BMI and CSF OP were significantly correlated (r = 0.476, P < 0.001, Pearson's correlation test). Obesity (defined as BMI > 30) was a predictor of increase in intracranial pressure (defined as OP > 200 mmH(2)O) (f = 17.26, 95% confidence interval 6.0, 8.6; P < 0.001). From our study we strongly recommend that not only intractable CM patients with high BMI, but also first diagnosed patients with BMI > 30 should be systematically evaluated by a LP to rule out IIHWOP.
Summary:Purpose: This study was performed to study the role of adenosine triphosphate (ATP) in the brain of pilocarpine-induced chronic epileptic rats.Methods: ATP-mediated changes in intracellular calcium were studied by the fura-2 method. Immunohistochemistry and Western blotting methods were used to localize and quantify P2X7 receptors in these animals.Results: The fluorometric study in chronic rats revealed a biphasic response indicating the presence of P2X7 receptors.The Western blotting study showed an increase of 80% of P2X7 expression in chronic rats compared with the control group. P2X7 immunoreactivity resembled mossy fiber sprouting at the dentate gyrus of epileptic animals.Conclusions: These results suggest that purinergic receptors may participate in the pathophysiology of temporal lobe epilepsy. Key Words: Epilepsy-ATP-P2X7-PilocarpineRat.The role of adenosine triphosphate (ATP) as a peripheral and central neurotransmitter is mediated by P2 purinoceptors (1). The response of ATP as a fast neurotransmitter is mediated by ionotropic P2X receptors that have a high permeability to calcium ions. Seven subtypes of these receptors have been cloned (P2X1-7), and some of them (P2X4, P2X6, and P2X7) are abundant in hippocampus, amygdala, thalamus, and cortex (2). In contrast to other subtypes, P2X7 can form a 900-Da pore when activated by ATP, and this pore can dialyze the cytoplasmatic content, producing a large change in the intracellular ion homeostasis (3). Moreover, in vitro study in hippocampal slices showed that ATP released by electrical stimulation of Schaffer collateralcommissural afferents take part in excitatory synaptic transmission (4). ATP released from nerve endings stimulates an increase in intracellular Ca 2+ in rat brain and can activate the microglia that are able to release several cytotoxic and protective substances (5,6). However, there is no evidence that ATP-mediated calcium entry plays a pathophysiologic role in epilepsy. This study was performed to study the ATP role in temporal lobe epilepsy (TLE) using pilocarpine-induced epileptic rats. Thus, we studied hippocampal ATP-mediated calcium influx, and we localized and quantified purinergic P2X7 receptors. METHODSChronic epileptic animals were obtained 60 days after status epilepticus induced by pilocarpine (380 mg/kg, i.p.). For the control group, a saline solution was used instead of pilocarpine. The intracellular calcium response mediated by ATP was measured with fluorometry. P2X7 expression was studied by immunohistochemistry (IHC) and quantified by Western blotting.For the fluorometric study, hippocampi slices were submitted to the fura-2 method described by Grynkiewicz et al. (7). In brief, rats from epileptic (n ס 5) and control (n ס 5) groups were killed, their brains removed and placed in cold artificial cerebrospinal fluid (aCSF) containing (in mM): 130 NaCl, 24 NaHCO 3 , 10 D-glucose, 1.3 NaH 2 PO 4 , 3.5 KCl, 5 MgCl, and 0.2 CaCl 2 . Afterward, the brains were sliced (500 m) in a vibratome. Hippocampal slices were inc...
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