Rat brain reactions to acute brain stem lesion on dynamics of parameters of cerebral electric activity

Despite an old history of a question, adaptive brain reactions that develop after an acute brainstem lesion have not been adequately investigated. With the aim to study the central mechanisms of compensation/decompensation and to specify the character of involvement of orbitofrontal cortex and hippocampus into these processes the spatiotemporal organization of brain electric activity was analyzed in 8 rats before and after electrolytic brainstem lesion at the level of the lateral vestibular nucleus Deiters (VND). The electric activity was recorded from symmetric frontal and somatosensory cortical areas, hippocampal areas CA1, and intact VND. Spectralcoherent analysis showed that adaptive reactions are most clearly manifested by changes in the spatiotemporal organization of the theata activity: 1) early brainstemhippocampal synchronization of the electric activity in the frequency range of 6-7 Hz with subsequent involvement of anterior cortical regions is characteristic of survived animals; 2) independent hippocampal-cortical hemispheric system of excitation in the frequency of 4-5 Hz precedes the fatal outcome. On the day before the fatal outcome the interhemispheric coherence in the orbitofrontal cortex dropped, which suggests the involvement of these brain regions into the processes of visceral regulation.     

N-Acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury

To evaluate the contribution of cellular dysfunction and neuronal loss to brain N-acetylaspartate (NAA) depletion, NAA was measured in brain tissue by HPLC and UV detection in rats subjected to cerebral injury, associated or not with cell death. When lesion was induced by intracarotid injection of microspheres, the fall in NAA was related to the degree of embolization and to the severity of brain oedema. When striatal lesion was induced by local injection of malonate, the larger the lesion volume, the higher the NAA depletion. However, reduction of brain oedema and striatal lesion by treatment with the lipophilic iron chelator dipyridyl (20 mg/kg, 1 h before and every 8 h after embolization) and the inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg given 1 h before malonate and then every 9 h), respectively, failed to ameliorate the fall in NAA. Moreover, after systemic administration of 3-nitropropionic acid, a marked reversible fall in NAA striatal content was observed despite the lack of tissue necrosis. Overall results show that cellular dysfunction can cause higher reductions in NAA level than neuronal loss, thus making of NAA quantification a potential tool for visualizing the penumbra area in stroke patients.     

Serotonin depletion produces long lasting increase in striatal glutamatergic transmission

The ability of serotonin (5-HT) to influence striatal glutamatergic transmission was examined by determining changes over time in glutamate extracellular levels, transporter expression and synaptosomal uptake in rats with lesion of serotonergic neurones. By 8 days after intraraphe injections of 5,7-dihydroxytryptamine, producing 80% decreases in striatal tissue 5-HT levels, no changes were observed in the glutamatergic transmission. When 5-HT depletion was almost complete (21 days post-lesion), high affinity glutamate uptake in striatal synaptosomal preparations was significantly increased (156% of control), although no changes in striatal GLT1, GLAST and EAAC1 mRNAs, and GLT1 protein were detected by in situ hybridization and immunohistochemistry. Meanwhile, the serotonin lesion produced large increases in basal extracellular levels of glutamate and glutamine (364% and 259%, respectively) determined in awake rats by in vivo microdialysis, whereas no change was observed in dopamine levels as compared with control rats. High potassium depolarization as well as L-trans-pyrrolidine-2,4-dicarboxylate, also induced larger increases in extracellular levels of glutamate in lesioned rats than in controls. Finally, similar changes in glutamate transmission were observed by 3 months post-lesion. These results suggest that 5-HT has a long lasting and tonic inhibitory influence on the striatal glutamatergic input, without affecting the basal dopaminergic transmission.     

CT appearance of experimental thalamic radiofrequency lesion in dog

The location and extent of thalamic lesions following thalamotomy can be identified as a large low density area in the acute stage to a small spot in the chronic stage. Stereotactic experimental radiofrequency lesions were placed in the thalamus of 35 mongrel dogs. CT images and whole brain specimens were obtained on days 0, 3, 7, 10, 14, 21 and 60. The appropriate time to map the lesions in the thalamus was thought to be about day 14, because of the thalamic size ratio and the correction of the ventricular deformity. The histological area of the lesion at day 14 corresponded better to the contrast-enhanced area than to that of the plain CT. These results suggest that the lesion demonstrated by contrast-enhanced CT scans at day 14 gives the best anatomical mapping of the actual histological defect.     

Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion

Selective lesion of rat basal forebrain by the cholinergic immunotoxin 192IgG-saporin was used as an animal model to address the question of whether the changes in cortical glucose metabolism observed in patients with Alzheimer's disease may be related to impaired cholinergic transmission. At different times after creating the immunolesion, the isoenzyme pattern and steady-state mRNA levels of the key glycolytic enzyme phosphofructokinase were determined in cortex, hippocampus, basal forebrain and nucleus caudatus. The loss of cholinergic input was accompanied by a persistent decrease in choline acetytransferase and acetylcholine esterase activities in the cortical target areas similar to the cholinergic malfunction seen in Alzheimer's dementia. The basal forebrain lesion induced by the immunotoxin resulted in a transient increase in phosphofructokinase activity peaking on day 7 after inducing the lesion in cortical areas. In parallel, an increased steady-state level of phosphofructokinase mRNA was determined by RT/real-time PCR and in situ hybridization. In contrast, analysis by western blotting and quantitative PCR revealed no changes in the phosphofructokinase isoenzyme pattern after immunolesion. It is concluded that common metabolic mechanisms may underlie the degenerative and repair processes in denervated rat brain and in the diseased Alzheimer's brain.     

Reduction in parvalbumin expression in the zona incerta after 6OHDA lesion in rats

In an effort to understand better the neurochemical changes that occur in Parkinson disease, we have examined the expression patterns of the calcium-binding protein parvalbumin in the zona incerta in parkinsonian rats. Sprague-Dawley rats had small volumes of either saline (control) or 6 hydroxydopamine (6OHDA) injected into the medial forebrain bundle, the major tract carrying dopaminergic nigrostriatal axons. After various post-lesion survival periods, ranging from 2 hrs to 84 days, rats were perfused with formaldehyde and their brains processed for routine tyrosine hydroxylase (TH) or parvalbumin immunocytochemistry. In the 3 to 84 days post-lesion cases, there was an overall 50% reduction in the number of parvalbumin⁺ cells in the zona incerta on the 6OHDA-lesioned side when compared to control. In the 2 hrs post-lesion cases, there was no substantial loss of parvalbumin⁺ cells in the zona incerta after 6OHDA lesion, although in these cases (unlike the longer survival periods), there was limited loss of TH⁺ cells in the midbrain on the lesion side. The loss of parvalbumin⁺ cells from the zona incerta was due to a loss of antigen expression rather than a loss of the cells themselves, since the number of Nissl-stained cells in the zona incerta was similar on the control and 6OHDA-lesioned sides. In summary, our results indicate that a loss of the midbrain dopaminergic cells induces a major change in parvalbumin expression within the zona incerta. This change may have key functional and clinical implications.     

Caffeic acid attenuates neuronal damage, astrogliosis and glial scar formation in mouse brain with cryoinjury

Traumatic brain injury induces neuron damage in early phase, and astrogliosis and the formation of the glial scar in late phase. Caffeic acid (3, 4-dihydroxycinnamic acid), one of the natural phenolic compounds, exerts neuroprotective effects against ischemic brain injuries with anti-oxidant and anti-inflammatory properties, and by scavenging reactive species. However, whether caffeic acid has protective effects against traumatic brain injury is unknown. Therefore, we determined the effect of caffeic acid on the lesion in the early (1 day) and late phases (7 to 28 days) of cryoinjury in mice. We found that caffeic acid (10 and 50 mg/kg, i.p., for 7 days after cryoinjury) reduced the lesion area and attenuated the neuron loss around the lesion core 1 to 28 days, but attenuated the neuron loss in the lesion core only 1 day after cryoinjury. Moreover, caffeic acid attenuated astrocyte proliferation, glial scar wall formation and glial fibrillary acidic protein (GFAP) protein expression in the late phase of cryoinjury (7 to 28 days). Caffeic acid also inhibited the reduction of superoxide dismutase activity and the increase in malondialdehyde content in the brain 1 day after cryoinjury. These results indicate that caffeic acid exerts a protective effect in traumatic brain injury, especially on glial scar formation in the late phase, which at least is associated with its anti-oxidant ability.     

Structural basis of developmental plasticity in the corticostriatal system

Previous studies have shown that in developing monkey corticostriatal fibres terminate around striatal cytoarchitectonic compartments--cell islands, showing transfiguration around 105th embryonic day (E105) of gestation. In the present study we have analyzed these striatal cytoarchitectonic islands and acetylcholinesterase (AChE) rich patches in the developing human brain considering them as structural indicators of the development of the corticostriatal pathways. Postmortal brain tissue of 27 fetuses and prematurely born infants, ranging from 11-34 postovulatory weeks (POW) whose deaths were attributed to non neurological causes, were processed by Nissl method, AChE histochemistry and imunocytochemical technique (synaptophysin). All specimens are part of the Zagreb Neuroembryological Collection. Initial AChE patches, presumably corresponding to the dopaminergic islands, were seen as early as 10 POW whereas cytoarchitectonical cell islands were not observed until 14 POW The main developmental change occurs between 20-24 POW when AChE negative cell poor zones develop around cell islands. This transient AChE pattern of striatal organization reaches its peak around 28 POW being most prominent along lateral border of putamen. In one case of periventricular hemorrhagic lesion with premortem survival period we have found reorganization of AChE patches in the putamen which indicates structural plasticity of corticostriatal pathways. In conclusion we propose that cell poor zones serve as waiting compartments for growing corticostriatal fibers which approach striatum through subcallosal bundle and external capsule. The period of the existence of striatal compartments (14-30 POW) is a sensitive period for structural plasticity and vulnerability after periventricular lesions.     

Activity of substantia nigra pars reticulata neurons after lesion of the ipsilateral neostriatum by kainic acid in rats

Huntington's chorea is a degenerative disorder of the human brain characterized by a marked loss of intrinsic neostriatal neurons. This situation can be reproduced by kainic acid injection in the caudate nucleus. Activity of pars reticulata neurons ipsilateral to the injected neostriatum was studied in normal, control (saline-injected) and lesioned rats. They were identified by electrophysiological and histological criteria (Fig. 1). Results obtained in normal and control rats were very similar (Table I). As previously described, the mean frequency of these neurons was high. An important percentage (respectively 72.5 and 73%) and these neurons presented the characteristics of a regular firing pattern (so called "organized neurons"). Results obtained in kainic acid lesioned rats were significantly different (Table I). The mean frequency was lower and only 11% of reticulata cells remained organized after neostriatal lesion. This important dysfunction may be explained in various ways: The neostriato-nigral pathway's destruction involves both the inhibitory GABAergic tract and the excitatory substance P tract (GALE et al., 1978). Other inputs arising from many structures in the brain continue to exert their own action on SN neurons, resulting in an unbalance in the SN inputs. It is well known that the nigral dopamine influences the neuronal activity of pars reticulata neurons (Ruffieux et Schultz, 1980; Waszczak et Walters, 1983). Doudet et al. (1984 b) previously reported a dysfunction of neuronal activity of dopaminergic cells after striatal lesion. A disturbance in the electrical activity may induce a similar disturbance in the intranigral dendritic release of DA.(ABSTRACT TRUNCATED AT 250 WORDS)     

CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke

We investigated the effect of CDP-choline on brain plasticity markers expression in the acute phase of cerebral infarct in an experimental animal model. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO) and treated or not with CDP-choline (500 mg/kg) daily for 14 days starting 30 min after pMCAO. Functional status was evaluated with Roger's test; lesion volume with magnetic resonance imaging (MRI) and hematoxylin and eosin staining (H&E); cell death with TUNEL; cellular proliferation with BrdU immunohistochemistry; vascular endothelial growth factor (VEGF), synaptophysin, glial fibrillary acidic protein (GFAP) and low-density lipoprotein receptor-related protein (LRP) by immunofluorescence and Western-blot techniques. CDP-choline significantly improved functional recovery and decreased lesion volume on MRI, TUNEL-positive cell number and LRP levels at 14 days. In addition, CDP-choline significantly increased BrdU, VEGF and synaptophysin values and decreased GFAP levels in the peri-infarct zone compared with the infarct group. In conclusion, our data indicate that CDP-choline improved functional recovery after permanent middle cerebral artery occlusion in association with reductions in lesion volume, cell death and LRP expression. In fact, CDP-choline increased cell proliferation, vasculogenesis and synaptophysin levels and reduced GFAP levels in the peri-infarct area of the ischemic stroke.     

Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain

The vesicular protein synaptobrevin contributes to two mutually exclusive complexes in mature synapses. Synaptobrevin tightly interacts with the plasma membrane proteins syntaxin and SNAP 25 forming the SNARE complex as a prerequisite for exocytotic membrane fusion. Alternatively, synaptobrevin binds to the vesicular protein synaptophysin. It is unclear whether SNARE complex formation is diminished or facilitated when synaptobrevin is bound to synaptophysin. Here we show that the synaptophysin-synaptobrevin complex is increased in adult rat brain after repeated synaptic hyperactivity in the kindling model of epilepsy. Two days after the last kindling-induced stage V seizure the relative amount of synaptophysin-synaptobrevin complex obtained by co-immunoprecipitation from cortical and hippocampal membranes was increased twofold compared to controls. By contrast the relative amounts of various synaptic proteins as well as that of the SNARE complex did not change in membrane preparations from kindled rats compared to controls. The increased amount of synaptophysin-synaptobrevin complex in kindled rats supports the idea that this complex represents a reserve pool for synaptobrevin enabling synaptic vesicles to adjust to an increased demand for synaptic efficiency. We conclude that the synaptophysin-synaptobrevin interaction is involved in activity-dependent plastic changes in adult rat brain.     

丁苯酞对脑梗死模型大鼠血清及脑组织突触素及突触后致密物-95表达的影响

摘要 目的：探讨丁苯酞对脑梗死模型大鼠血清及脑组织突触素及突触后致密物（postsynaptic density,PSD）-95表达的影响。方法：将建模成功的大鼠随机平分为三组-丁苯酞组、阿司匹林组与模型组各18只。三组分别给予腹腔注射丁苯酞注射液20 mg/kg+阿司匹林20 mg/kg、阿司匹林20 mg/kg与等体积的生理盐水,1次/d,检测血清及脑组织突触素及PSD-95表达变化情况。结果：（1）治疗第7 d与治疗第14 d后,丁苯酞组和阿司匹林组大鼠改良神经功能评分（Modified neurological severity scores,mNSS）均显著低于模型组（P<0.05）,丁苯酞组低于阿司匹林组（P<0.05）;（2）治疗第7 d与治疗第14 d,丁苯酞组、阿司匹林组大鼠的脑梗死体积百分比均显著低于模型组（P<0.05）,丁苯酞组低于阿司匹林组（P<0.05）;（3）治疗第7 d与治疗第14 d,丁苯酞组、阿司匹林组大鼠血清突触素及PSD-95表达水平均显著高于模型组（P<0.05）,丁苯酞组高于阿司匹林组（P<0.05）;（4）治疗第7 d与治疗第14 d后,丁苯酞组、阿司匹林组大鼠大脑组织突触素及PSD-95蛋白相对表达水平均显著高于模型组（P<0.05）,丁苯酞组高于阿司匹林组（P<0.05）。结论：丁苯酞在脑梗死模型大鼠的应用可促进大鼠血清及脑组织突触素及PSD-95的表达,并减小脑梗死面积,因而有利于大鼠的神经功能的恢复。     

Synaptosomal Protein Kinase C Subspecies: A. Dynamic Changes in the Hippocampus and Cerebellar Cortex Concomitant with Synaptogenesis

The expression of protein kinase C (PKC) subspecies in synaptosomes prepared from a number of adult brain regions was compared. Cerebral cortical and thalamic/striatal synaptosomes were found to express three peaks of enzyme activity upon hydroxyapatite chromatography, corresponding to the type I(gamma), type II(beta), and type III(alpha) subspecies. Synaptosomes prepared from either the hippocampus or the cerebellar cortex, however, contained only two major peaks, corresponding to the alpha- and beta-subspecies, with barely detectable levels of the gamma-subspecies, even though these tissue areas were enriched in the latter enzyme. When the ontogenic pattern of hippocampal synaptosomal PKC subspecies was examined, it was found that at postnatal day 7, significant quantities of the gamma-subspecies were present and that this subspecies reached its peak levels at around postnatal day 14, before steadily declining to its adult level. Similar changes were observed also for the gamma-subspecies in cerebellar cortex synaptosomes. The dynamic changes in the synaptosomal PKC subspecies take place at a critical period in the development of the rat brain, concomitant with an active period of synaptogenesis, suggesting that it may play a role in synaptogenesis.     

Suloctidil increases the rat brain cortex microvascular regeneration after a lesion

A "cavity" lesion made by aspiration in the rat occipital cortex induces a parenchymal and a vascular reaction in its vicinity. The first was mainly characterized by cellular necrosis and gliosis, the second by an increase of the vascular network. In vehicle treated rats, a 50% significant increase of the vascular network was observed around the cavity 4 days after the lesion, in comparison to the uninjured contralateral cortex. The effects of a vasoactive substance, suloctidil, on the vascular reaction was studied in the brain cortex. A single oral dose of suloctidil (30 mg/kg; 2 hours before the sacrifice) gave the same effect as the vehicle group. After 8 days of suloctidil oral administration (30 mg/kg; twice daily: 4 days before lesion and 4 days after) a significant increase (123%) of the vascular network was observed around the cavity. The hypothetical ways by which a chronic treatment of suloctidil induces this increase of the neovascularization observed after cortical lesion are discussed.     

Quinolinic acid lesion induces changes in rat striatal glutathione metabolism

Although the involvement of oxidative mechanisms in the cytotoxicity of excitatory amino acids has been well documented, it is not known whether the intrastriatal injection of quinolinic acid (QA) induces changes in glutathione (GSH) metabolism. In this work, the activities of the enzymes GSH reductase (GRD), GSH peroxidase (GPX), and GSH S-transferase (GST), as well as the GSH content, were studied in the striatum, hippocampus, and frontal cortex of rats 1 and 6 weeks following the intrastriatal injection of QA (225 nmol). One group of animals remained untreated. This lesion resulted in a 20% decrease in striatal GRD activity at both the 1- and 6-week postlesion times, whereas GST exhibited a 30% activity increase in the lesioned striatum observable only 6 weeks after the lesion. GPX activity remained unchanged. In addition, the QA injection elicited a 30% fall in GSH level at the 1-week postlesion time. GSH related enzyme activities and GSH content from other areas outside the lesioned striatum were not affected. GST activation could represent a beneficial compensatory response to neutralize some of the oxidant agents generated by the lesion. However, this effect together with the reduction in GRD activity could be the cause or a contributing factor to the observed QA-induced deficit in GSH availability and, consequently, further disrupt the oxidant homeostasis of the injured striatal tissue. Therefore, these results provide evidence that the in vivo excitotoxic injury to the brain might affect oxidant/antioxidant equilibrium by eliciting changes in glutathione metabolism.     

Developmental-stage-dependent radiosensitivity of neural cells in the ventricular zone of telencephalon in mouse and rat fetuses

Pregnant ICR mice were treated with single whole-body X-radiation at a dose of 0.24 Gy on day 10, 13, or 15 of gestation. Fetuses were obtained from mothers during 1 and 24 hours after irradiation. Pyknotic cells in the ventricular zone of telencephalon were counted in serial histological sections. Incidence of pyknotic cells peaked during 6 and 9 hours after irradiation in each gestation day group. Then, dose-response curves were obtained 6 hours after 0-0.48 Gy of irradiation. All three dose-response curves showed clear linearity in the dose range lower than 0.24 Gy. Ratios of radiosensitivity estimated from the slopes of dose-response curves in day 10, 13, and 15 groups were 1, 1.4, and 0.4, respectively. These demonstrated that ventricular cells in the day 13 fetal telencephalon were the most radiosensitive among the three different age groups. In order to confirm the presence of the highly radiosensitive stage common to mammalian cerebral cortical histogenesis, pregnant F344 rats were treated with single whole-body gamma-irradiation at a dose of 0.48 Gy on day 13, 14, 15, 17, or 19 of gestation. The incidence of pyknotic cells in the ventricular zone of telencephalon was examined microscopically during 1 and 24 hours after irradiation. The peak incidence was shown 6 hours after irradiation in all the treated groups, and the highest peak incidence was shown in day-15-treated group. The developmental stage of telencephalon of day 15 rat fetuses was comparable to that of day 13 mouse fetuses. Thus, the highest radiosensitivity in terms of acute cell death was shown in the same developmental stage of brain development, i.e., the beginning phase of cerebral cortical histogenesis, in both mice and rats.     

Chronic histological effects of ultrasonic hyperthermia on normal feline brain tissue

The histopathological changes associated with ultrasonic heating of normal cat brain have been correlated with thermal distributions. Ultrasound energy was applied for 50 min at different intensities to generate tissue temperatures from 42 to 48 degrees C. Animals were sacrificed at various intervals from 1 to 56 days. The organization and resolution of thermal damage was characterized by three stages of histopathological changes within the nervous tissue. The acute stage (Days 1-3) was defined by (1) extensive coagulation necrosis, (2) pyknosis of neuronal elements in the gray matter, (3) edema and vacuolation in the white matter, and (4) polymorphonuclear leukocytes. The subacute stage (Days 3-21) was characterized by (1) the appearance of lipid-laden macrophages, (2) liquefaction of the necrotic regions, (3) fibroblastic proliferation, and (4) vascular proliferation with some perivascular inflammatory infiltration (lymphocytes). Lastly, the chronic stage (Days 21-56) was defined by (1) fibrosis (reticulin and collagen formation) and (2) gliosis (reactive astrocytic proliferation) occurring around the fluid-filled necrotic center. Analysis of these data has also included a study of the lesion size versus the dose (temperature for 50 min) of heating. The results demonstrate a significant linear dose-response correlation. The results of this study indicate that the histological appearance and time course of repair of thermal injury in the normal brain tissue are analogous to acute brain necrosis resulting from cerebral infarction, except the thermal damage does not result in significant hemorrhage.     

Transient contralateral rotation following unilateral substantia nigra lesion reflects susceptibility of the nigrostriatal system to exhaustion by amphetamine

Following unilateral 6-OHDA induced SN lesion, a transient period of contralateral rotation has been reported to precede the predominant ipsilateral circling. In order to clarify the nature of this initial contralateral rotation we examined the effect of the duration of recovery period after the lesion, on amphetamine-induced rotational behavior. Three days post lesion, most rats circled predominantly contralaterally to the lesion. Such contralateral rotation may result from either degeneration-induced breakdown of the DA pool, or lesion-induced increase of DA turnover in the spared neurons. A substantial degree of contralateral preference was still evident when amphetamine was administered for the first time 24 days after lesioning, indicating involvement of spared cells in the contralateral rotation. However, regardless of the duration of recovery (and irrespective of either lesion volume, amphetamine dose, or post-lesion motor exercise), amphetamine-induced rotation tended to become gradually more ipsilateral as the observation session progressed, and all rats circled ipsilaterally to the lesion in response to further amphetamine injections. These findings suggest that amphetamine has an irreversible effect on the post-lesion DA pool contributing to contralateral rotation.     

Evidence for genistein mediated cytotoxicity and apoptosis in rat brain

The effects of chronic treatment with high doses of genistein, a major isoflavone of soybeans and soy-based products, have yet to be determined and what is known remains controversial. The present study was undertaken to investigate the cytotoxic effects of chronic ingestion of genistein on rat brain in vivo and the observations were compared with results from in vitro studies with primary cultures of cortical neurons. Sprague-Dawley rats were given 2 or 20 mg/day genistein (p.o.) for four weeks. The high dose of genistein (20 mg/day) significantly increased lactate dehydrogenase (LDH) in rat brain tissue homogenates, whereas the low dose of genistein (2 mg/day) decreased LDH. In addition, DNA fragmentation was detected in homogenates of brain tissue from rats receiving either dose of genistein. These results are consistent with those of in vitro studies indicating that high concentrations of genistein caused cytotoxicity and DNA ladder formation in primary cultures of cortical neurons. Genistein decreased the expression of the 32 kDa caspase-3 precursor and increased the levels of cleaved caspase-3 (18 kDa) in both rat brain tissue homogenates and in primary cultures of cortical neurons. Furthermore, expression of poly (ADP-ribose) polymerase (PARP) was also decreased in both experimental systems. These results suggest that chronic administration of genistein at high doses may induce cytotoxicity and apoptosis in the rat brain.