Lateral Cerebral Cortex Research Articles

Genetic tagging of the adenosine A2A receptor reveals its heterogeneous expression in brain regions.

The adenosine A2A receptor (A2AR), a G protein-coupled receptor, is involved in numerous and varied physiological and pathological processes, including inflammation, immune responses, blood flow, and neurotransmission. Accordingly, it has become an important drug target for the treatment of neuropsychiatric disorders. However, the exact brain distribution of A2AR in regions outside the striatum that display relatively low levels of endogenous A2AR expression has hampered the exploration of A2AR functions under both physiological and pathological conditions. To further study the detailed distribution of the A2AR in low-expression regions, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice) via CRISPR/Cas9 technology. Here, using CRISPR/Cas9 technology, we have generated A2AR knock-in mice in which the 3xHA-2xMyc epitope tag sequence was fused to the C-terminus of A2AR (A2AR-tag mice). The A2AR-tag mice exhibited normal locomotor activity and emotional state. Consistent with previous studies, A2AR fluorescence was widely detected in the striatum, nucleus accumbens, and olfactory tubercles, with numerous labeled cells being evident in these regions in the A2AR-tag mouse. Importantly, we also identified the presence of a few but clearly labeled cells in heterogeneous brain regions where A2AR expression has not previously been unambiguously detected, including the lateral septum, hippocampus, amygdala, cerebral cortex, and gigantocellular reticular nucleus. The A2AR-tag mouse represents a novel useful genetic tool for monitoring the expression of A2AR and dissecting its functions in brain regions other than the striatum.

Establishment of a system for regulating the gene expression of embryonic mouse cerebral cortex neural stem cells by in utero electroporation

To establish a system for regulating the gene expression of embryonic mouse cerebral cortex neural stem cells (NSCs) using in utero electroporation (IUE). At embryonic day 14.5, the mouse cerebral cortex NSCs were electro-transfected with the pCIG plasmid injected into the ventricle of the mouse embryo. At embryonic day 16.5 or day 17.5, embryonic mouse brain tissues were collected to prepare frozen sections. Immunofluorescence staining was used to observe the proliferation, apoptosis, division, directional differentiation, migration, and maturation of NSCs. The differentiation of NSCs into intermediate progenitors, the proliferation and apoptosis of NSCs, and the morphological development of radial axis of radial glial cells were observed at embryonic day 16.5. The differentiation of NSCs into neurons in layers V-VI of the cerebral cortex, the migration of NSCs to the lateral cerebral cortex, the development of dendrites of migrating neurons, and the maturation of neurons were observed at embryonic day 17.5. The system for regulating the gene expression of embryonic mouse cerebral cortex NSCs can be established using IUE, which is useful for the study of neural development related to the proliferation, apoptosis, division, directional differentiation, migration and maturation of NSCs in the cerebral cortex.

Probabilistic mapping of thalamic nuclei and thalamocortical functional connectivity in idiopathic generalised epilepsy.

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear‐specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non‐refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting‐state functional magnetic resonance imaging (MRI) in patients with refractory and non‐refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed‐to‐voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non‐refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non‐refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting‐state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE.

Transformation of speech sequences in human sensorimotor circuits

After we listen to a series of words, we can silently replay them in our mind. Does this mental replay involve a reactivation of our original perceptual dynamics? We recorded electrocorticographic (ECoG) activity across the lateral cerebral cortex as people heard and then mentally rehearsed spoken sentences. For each region, we tested whether silent rehearsal of sentences involved reactivation of sentence-specific representations established during perception or transformation to a distinct representation. In sensorimotor and premotor cortex, we observed reliable and temporally precise responses to speech; these patterns transformed to distinct sentence-specific representations during mental rehearsal. In contrast, we observed less reliable and less temporally precise responses in prefrontal and temporoparietal cortex; these higher-order representations, which were sensitive to sentence semantics, were shared across perception and rehearsal of the same sentence. The mental rehearsal of natural speech involves the transformation of stimulus-locked speech representations in sensorimotor and premotor cortex, combined with diffuse reactivation of higher-order semantic representations.

Different characteristics of cell volume and intracellular calcium ion concentration dynamics between the hippocampal CA1 and lateral cerebral cortex of male mouse brain slices during exposure to hypotonic stress.

The mechanism of brain edema is complex and still remains unclear. Our aim was to investigate the regional differences of cell volume and intracellular Ca2+ concentration ([Ca2+ ]i ) dynamics during hypotonic stress in male mouse hemi-brain slices. Brain slices were loaded with the fluorescence Ca2+ indicator fura-2, and cell volume and [Ca2+ ]i in the lateral cerebral cortex (LCC) and hippocampal CA1 (CA1) region were measured simultaneously during exposure to hypotonic stress using Ca2+ insensitive (F360) and Ca2+ sensitive fluorescence (F380), respectively. Brain cell swelling induced by hypotonic stress was followed by a regulatory volume change that coincided with an increase in [Ca2+ ]i . The degrees of change in cell volume and [Ca2+ ]i were significantly different between the LCC and CA1. The increase in cell volume and [Ca2+ ]i in the LCC, but not in the CA1, was decreased by the transient receptor potential channel blockers LaCl3 and GdCl3 . The increase in [Ca2+ ]i in both the LCC and CA1, was significantly decreased by the intracellular Ca2+ modulators thapsigargin and xestospongin C. The K+ channel activator isoflurane and Cl- channel blocker NPPB significantly decreased [Ca2+ ]i in the LCC. This study demonstrated that, between cells located in the LCC and in the CA1, the characteristics of brain edema induced by hypotonic stress are different. This can be ascribed to the different contribution of volume sensitive G-protein coupled receptor and stretch sensitive Ca2+ channels.

Progressive histomorphometric analysis of the lateral ventricle and cerebral cortex of Wistar rats following kaolin-induced hydrocephalus

Context: Hydrocephalus results in ventriculomegaly following excess production and/or impaired drainage of cerebrospinal fluid. The lateral ventricle (LV) is surrounded by critical structures such as hippocampus and thalamus; its enlargement will adversely impact surrounding brain structures including the cerebral cortex. Aims: This study aims to evaluate the morphometry of cerebral cortex and LV in hydrocephalus over 4 weeks. Settings and Design: Fifty-one 3-week-old rats were divided into Groups A (experimental = 6; control = 5), B (experimental = 8; control = 6), C (experimental = 8; control = 6) and D (experimental = 6; control = 6), sacrificed at the end of 1, 2, 3 and 4 weeks, respectively. Materials and Methods: Experimental rats were induced by injection of 0.04 ml of 200 mg/ml kaolin suspension into the cisterna magnum under ketamine (90 mg/kbw) and diazepam (12.5 mg/kbw) anaesthesia. Rats were sacrificed by cervical dislocation and brain fixed in 10% formal saline. Brain slices at the level of the optic chiasma were processed and stained with haematoxylin and eosin. Statistical Analysis Used: One-way ANOVA and Student–Newman–Keuls test. Results: In experimental rats, lethargy, poor feeding, globular head and exophthalmos were noted. The LV width and the LV/cortical thickness (CT) ratio were significantly increased from the 1st to the 4th post-induction week (P Conclusions: White matter/cortical thinning and ventriculomegaly are acute-phase features, although cortical thinning lags behind others. Detachment of the choroid plexus and reversal of SWM thinning are features of chronicity.

Exposure system to study hypotheses of ELF and RF electromagnetic field interactions of mobile phones with the central nervous system

A novel exposure system for double-blind human electromagnetic provocation studies has been developed that satisfies the precision, control of fields and potential artifacts, and provides the flexibility to investigate the response of hypotheses-driven electromagnetic field exposure schemes on brain function, ranging from extremely low frequency (ELF) to radio frequency (RF) fields. The system can provide the same exposure of the lateral cerebral cortex at two different RF frequencies (900 and 2140 MHz) but with different exposure levels at subcortical structures, and also allows uniform ELF magnetic field exposure of the brain. The RF modulation and ELF signal are obtained by a freely programmable arbitrary signal generator allowing a wide range of worst-case exposure scenarios to be simulated, including those caused by wireless devices. The maximum achievable RF exposure is larger than 60 W/kg peak spatial specific absorption rate averaged over 10 g of tissue. The maximum ELF magnetic field exposure of the brain is 800 A/m at 50 Hz with a deviation from uniformity of 8% (SD).

Neuronal classes in the corticoid complex of the telencephalon of the strawberry finch, Estrilda amandava

The present study, based on neurohistological techniques (Nissl-staining, Golgi-impregnation), focuses on the cytoarchitecture of the corticoid complex in the strawberry finch, Estrilda amandava. This complex in birds occupies the dorsolateral surface of the telencephalic pallium and remains subdivided into an intermediate corticoid area (CI) and a dorsolateral corticoid area (CDL). The CDL in the strawberry finch is a thin superficial part of the caudal pallium adjoining the medially situated hippocampal formation, whereas the CI is demarcated between the CDL and the parahippocampal area of telencephalon. Neurons of the corticoid complex are classified into three main cell groups: predominant projection neurons, local circuit neurons and stellate neurons. The spinous projection neurons send out distant projecting axons that typically extend several varicose collaterals. Most of these collaterals lie parallel to the ventricle. These neurons are subclassified into pyramidal neurons (localized only in the CI) and multipolar neurons (present in both the CI and CDL). The CDL also possesses small and medium-sized horizontal cells, which are bitufted or multipolar with smooth, moderately branching dendrites. The aspinous local circuit neurons extend short axons that ramify locally. Stellate neurons have sparse spinous dendrites and locally arborizing axons. The corticoid complex of birds corresponds to the lateral cerebral cortex of lizards and to the entorhinal cortex of mammals on the basis of neuronal morphology and bidirectional connections between adjacent areas.

Cortical Damage in Alzheimer’s Disease: Estimation in Medial and Lateral Aspects of the Cerebrum using an Improved Mapping Method based on Diffusion-Weighted Magnetic Resonance Imaging

A method of estimating and mapping the cortical damage resulting from neurodegenerative diseases based on diffusion-weighted imaging was recently proposed. We improved on this method to visualize the cortical damage in Alzheimer's disease (AD) in the lateral and medial aspects of the cerebral hemispheres and to provide anatomic references. Damage in the cerebral cortex was estimated based on diffusivity in the subcortical white matter according to a previously published method. A map of subcortical mean diffusivity (MD) was superimposed on the corresponding anatomic image so that the spatial extent of the abnormality could be anatomically localized. The right and left hemispheres were separated to evaluate the medial and lateral aspects of each hemisphere. This method was applied to 10 healthy subjects and 11 AD patients. MDs within 20 cortical regions were visually evaluated and statistically compared between AD and healthy subjects at a significance level of P < .01. In addition to the involvement of the lateral aspects of the bilateral parietal and temporal lobes and clear sparing of the bilateral pericentral regions that were previously reported, significant MD elevation was observed in the medial aspects of the right frontal, bilateral parietal, and right temporal lobes. The extent of MD abnormalities was easily identified by the background anatomic image. Results suggested that AD damage in the lateral and medial cerebral cortex can be visualized with an anatomic reference using our method.

Histopathologic and neurobehavioral evaluation of a standardized fluid percussion model of brain trauma in the rat

For 5 male Sprague Dawley rats/group: Group 1 had a craniotomy; Group 2 had a craniotomy with a temporary luer lock fitting applied; and Group 3 additionally had a fluid percussive injury of approximately 5.5 atmospheres through the temporary luer lock to the exposed right lateral cerebral cortex. The skull defect was closed and behavioral assessments were performed at 2 hours after recovery from anesthesia, and again on Days 1, 3 and 14 post insult. The group given fluid percussion had deficits on balance beam, catalepsy and startle responses on day 0 that resolved at later timepoints. After 2 weeks, rats were euthanized under anesthesia and their brains were perfused in situ. Brains were trimmed at 2 mm intervals. Tissue loss at the cerebral cortical surface was estimated from H&E-stained sections using an ocular grid and averaged 2.3,1.9, and 6.1 mm2 respectively. In addition to greater loss of cerebral cortical tissue, the fluid percussion group had focal gliosis in the white matter, and focal neuronal degeneration visible with Fluoro Jade B staining in the deep cortex ventral and lateral to the site, as well as increased GFAP staining in the ipsilateral dorsal thalamus. Perl's stain showed traces of iron consistent with previous hemorrhage at the site in all groups and in the deeper areas of gliosis in Group 3.

Purkinje Cell Vulnerability to Mild and Severe Forebrain Head Trauma

Pathophysiological changes in the cortex, thalamus, and hippocampus have been implicated as contributors to motor and cognitive deficits in a number of animal models of traumatic brain injury (TBI). Indirect cerebellar injury may contribute to TBI pathophysiology because impairment of motor function and coordination are common consequences of TBI, but are also domains associated with cerebellar function. However, there is a lack of direct evidence to support this claim. Hence, in this study, a dose-response relationship of the cerebellum's susceptibility was determined at four grades of fluid percussion injury (1.5, 2.0, 2.5, and 3.0 atm) applied in the right lateral cerebral cortex of adult male Sprague-Dawley rats. Evidence suggests primary and secondary injury mechanisms resulting in selective cerebellar Purkinje neuron (PN) loss, whereas interneurons of the molecular layer were spared. The posterior region of the cerebellar vermis displayed significant PN loss (p = 0.001) at 1 day postinjury, whereas the gyrus of the horizontal fissure and gyrus of lobules III and IV exhibited delayed PN loss at higher levels of injury severity. Interestingly, neither terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) or cleaved caspase-3 colocalized with PNs at any time point or injury severity. Expression of calbindin-28k increased in regions of greatest PN loss, suggesting that the surviving PNs possess higher calcium-buffering capacities, which may account for their survival.

Spatio-temporal profile of small heat-shock protein Hsp27 induction in rat brain following fluid-percussion injury to the lateral parietotemporal cerebral cortex; involvement with beta actin

Heat shock protein 27 (Hsp27) belongs to a group of small Hsps that perform a variety of functions including molecular chaperoning, regulation of actin dynamics and antioxidative activity, and inhibition of apoptosis. In adult rat brain, constitutive neuronal expression of Hsp27 is present in neurons and occasionally non-neuronal cells including astrocytes, ependymal cells and the choroid plexus. Since little is currently known of the involvement of Hsp27 in cerebral trauma, we have examined the effects of moderate fluid-percussion injury (FPI) on the spatio-temporal patterns of Hsp27 induction and potential interaction of Hsp27 with other structural proteins in rat brain. In the ipsilateral parieto-temporal cortex, Hsp27 protein levels were increased over 7-fold at 24 h following the insult compared to sham controls by immunoblotting (Figure 1A), and which persisted for up to 7 days post-trauma. Immunohistochemical assessment revealed a mainly astroglial pattern of staining for Hsp27 in the cortex, hippocampus, and thalamic nuclei ipsilateral to the injury with some immunoreactivity also extending into contralateral hippocampal structures. Immunoprecipitation studies using both injured and contralateral cortical brain tissue of 24 h post-injured rats showed that Hsp27 immunoprecipitated only from the injured, but not contralateral, cortex at 24 h post-injury (Figure 1B). In addition, Hsp27 immunoprecipitate from 24 h post-injured ipsilateral cortex coimmunoprecipitated with beta actin, and not GFAP (Figure 1C). Our results suggest that FPI produces a large, predominantly astroglial-specific induction of Hsp27 that is widespread in the injured hemisphere. Given its previously identified role as a chaperone protein, interaction of Hsp27 with actin may indicate an important function for this gene in stabilization of actin filaments in astroglia, a potentially valuable contributing factor to the known resistance of these cells to trauma-induced stress.

Immunohistochemical Studies Concerning the Neuronal Cell Cycle of the Cat using PCNA, Ki‐67 and p53 Markers

Recent studies about parvovirus replication in mature neurones of cats indicate that even feline neurones do not seem to be terminally differentiated. For further determination of the proliferative capability of feline neurones, an immunohistochemical study investigating the neuronal expression of the cell cycle-related proteins, proliferating cell nuclear antigen (PCNA), Ki-67 and p53 was initiated. Brains of 50 cats of different age and gender, dying of various diseases, were examined. Strong PCNA clone PC10 expression could be observed in neurones of the cerebellar cortex and the vestibular nuclei, whereas entorhinal cortex, lateral geniculate nucleus and cerebral cortex revealed only weak immunolabelling. The PCNA clone 19F4 labelled numerous neurones in vestibular nuclei and some Purkinje cells of the cerebellum. Nuclear expression of Ki-67 was sporadic in the vestibular nuclei, but p53 expression could not be detected anywhere in the feline brain. However, the presence of nuclear PCNA and Ki-67 expression indicates that certain feline neurones are capable of re-entering the cell cycle.

Distribution of Histamine-Containing Neurons in the Laboratory Shrew (Suncus murinus) Brain.

The distribution of histamine (HIS)-containing neurons was studied by the avidin-biotin peroxidase complex (ABC) method, and compared with that of the monoaminergic and aromatic L-amino acid decarboxylase-positive neurons (D neurons) in the laboratory shrew (Suncus murinus) brain. In the laboratory shrew brain, HIS-immunoreactive (IR) neurons were strictly confined to the mammillary area. Packed clusters of HIS-IR neurons were localized to four regions: the dorsal and ventral premammillary nucleus, lateral mammillary nucleus and the posterior hypothalamic nucleus. HIS-IR nerve fibers were found mainly in the diencephalon and telencephalon. In particular, dense histaminergic innervation was observed in the preoptic area, bed nucleus of the stria terminalis and suprachiasmatic nucleus. Some HIS-IR nerve fibers were detected in the paraventricular nucleus, anterior hypothalamic nucleus, lateral septal nucleus and cerebral cortex. Few HIS-IR nerve fibers were found in the caudate nucleus, medial septal nucleus, colliculus, hippocampus and locus coeruleus. Comparison of the distribution of HIS-IR neurons with those of monoaminergic neurons and D neurons in the laboratory shrew brain revealed the following findings, which are unique to the laboratory shrew: 1) The distribution of HIS IR neurons was localized to a specific area. 2) Although HIS-IR nerve fibers were densely distributed in the median eminence in the rat brain, only a small number of HIS-IR nerve fibers were observed in this area in the laboratory shrew.

Intracisternal antisense oligonucleotide to growth associated protein-43 blocks the recovery-promoting effects of basic fibroblast growth factor after focal stroke.

Focal infarction (stroke) of the lateral cerebral cortex of rats (including the sensorimotor cortex) produces deficits in sensorimotor function of the contralateral limbs that recover partially over time. In previous studies, we found that the intracisternal injection of basic fibroblast growth factor (bFGF), a potent neurotrophic growth factor, starting at 1 day after stroke, significantly enhanced recovery of sensorimotor function of the contralateral forelimb and hindlimb. Moreover, immunoreactivity (IR) for growth-associated protein-43 (GAP-43), a molecular marker of new axonal growth, was increased in the intact contralateral sensorimotor cortex following bFGF treatment. In the current study, we found that the intracisternal administration of antisense, but not missense, oligonucleotide to GAP-43 blocked the recovery-enhancing effects of bFGF and blocked the increase in GAP-43 IR in the contralateral cortex. These results suggest that upregulation of GAP-43 expression and consequent enhanced axonal sprouting in intact uninjured parts of the brain are likely mechanisms for the recovery-promoting effects of bFGF.

Cannabinoid receptor and WIN-55,212-2-stimulated [ 35S]GTP γS binding and cannabinoid receptor mRNA levels in several brain structures of adult male rats chronically exposed to R-methanandamide

We and others have recently demonstrated that the pharmacological tolerance observed after prolonged exposure to plant and synthetic cannabinoids in adult individuals seems to have a pharmacodynamic basis, based on the observed down-regulation of cannabinoid receptors in the brain of cannabinoid-tolerant rats. However, we were unable to elicit a similar receptor down-regulation after a chronic exposure to anandamide, the first discovered endogenous cannabinoid, possibly because of its rapid metabolic breakdown in arachidonic acid and ethanolamine. The present study was designed to progress in these previous studies, by using R-methanandamide, a more stable analog, instead anandamide. In addition, we examined not only cannabinoid receptor binding, but also WIN-55,212-2-stimulated [ 35S]-GTP γS binding, by autoradiography, and cannabinoid receptor mRNA levels, by in situ hybridization. Results were as follows. The daily administration of R-methanandamide for a period of five days produced decreases in cannabinoid receptor binding in the lateral caudate-putamen, cerebellum, entopeduncular nucleus and substantia nigra. The remaining areas, the medial caudate-putamen, globus pallidus, cerebral cortex (layers I and VI), hippocampus (dentate gyrus and Ammon’s horn) and several limbic structures (nucleus accumbens, septum nuclei and basolateral amygdaloid nucleus), exhibited no changes in cannabinoid receptor binding. Similarly, the levels of cannabinoid receptor mRNA expression decreased in the lateral and medial caudate-putamen and in the CA1 and CA2 subfields of the Ammon’s horn in the hippocampus after the chronic exposure to R-methanandamide, whereas the remaining areas showed no changes. WIN-55,212-2-stimulated [ 35S]-GTP γS binding did not change in the lateral caudate-putamen, cerebral cortex (layer I), septum nuclei and hippocampal structures (dentate gyrus and Ammon’s horn) of animals chronically exposed to R-methanandamide, whereas a certain trend to decrease could be observed in the substantia nigra and deep layer (VI) of the cerebral cortex in these animals. In summary, as reported for other cannabinoid receptor agonists, the prolonged exposure of rats to R-methanandamide, a more stable analog of anandamide, was able to produce cannabinoid receptor-related changes in contrast with the absence of changes observed early with the metabolically labile anandamide. The observed changes exhibited an evident regional pattern with areas, such as basal ganglia, cerebellum and hippocampus, responding to chronic R-methanandamide treatment while regions, such as the cerebral cortex and limbic nuclei, not responding.

Effects of functional disruption of lateral pericentral cerebral cortex on primate swallowing

Bilateral cold block of the intracortical microstimulation (ICMS)-defined swallow cortex markedly affected the ability of monkeys to carry out swallowing. Significant changes also occurred in swallow-related electromyographic (EMG) activity patterns. These findings provide further evidence that the lateral pericentral cortex plays a critical role in the initiation and regulation of swallowing in the primate.

Chronic microelectrode investigations of normal human brain physiology using a hybrid depth electrode.

Neurosurgeons have unique access to in vivo human brain tissue, and in the course of clinical treatment important scientific advances have been made that further our understanding of normal brain physiology. In the modern era, microelectrode recordings have been used to systematically investigate the cellular properties of lateral temporal cerebral cortex. The current report describes a hybrid depth electrode (HDE) recording technique that was developed to enable neurosurgeons to simultaneously investigate normal cellular physiology during chronic intracranial EEG recordings. The HDE combines microelectrode and EEG recordings sites on a single shaft. Multiple microelectrode recordings are obtained from MRI defined brain sites and single-unit activity is discriminated from these data. To date, over 60 HDEs have been placed in 20 epilepsy surgery patients. Unique physiologic data have been gathered from neurons in numerous brain regions, including amygdala, hippocampus, frontal lobe, insula and Heschl's gyrus. Functional activation studies were carried out without risking patient safety or comfort.

Protection by NMDA receptor antagonists against seizures induced by intracerebral administration of 4-aminopyridine

The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and generalized tonic convulsions. This behavioral pattern appeared 5–9 min after administration of 4-aminopyridine and persisted for 100–150 min. 4-Aminopyridine also generated epileptiform electroencephalographic (EEG) discharges characterized by isolated spikes, poly-spikes and spike-wave complexes, which began some seconds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists (±)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), (±)-2-amino-7-phosphono-heptanoic acid (AP7) and (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alterations induced by i.c.v. 4-aminopyridine, particularly the tonic convulsions, but were less effective against those produced by i.cx. 4-aminopyridine. These antagonists also delayed the appearance of EEG epileptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-aminopyridine. These results, together with previous data showing that 4-aminopyridine stimulates the release of glutamate in vivo, suggest that an excessive glutamatergic neurotransmission involving NMDA receptors is implicated in 4-aminopyridine-induced seizures.

Posttreatment with intravenous basic fibroblast growth factor reduces histopathological damage following fluid-percussion brain injury in rats.

The purpose of this study was to determine whether treatment with intravenous basic fibroblast growth factor (bFGF) would protect histopathologically in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, the fluid-percussion interface was positioned parasagittally over the right cerebral cortex. On the second day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane, and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37-37.5 degrees C), rats were injured with a fluid-percussion pulse ranging from 1.6 to 1.9 atm. Rats were randomized into two groups where either bFGF (45 micrograms/kg/h) in vehicle (n = 7) or vehicle alone (n = 7) was infused intravenously for 3 h, beginning 30 min after TBI. Three days later, brains were perfusion-fixed for histopathological assessment and quantitative analysis of contusion volume and numbers of necrotic cortical neurons. In vehicle-treated animals, necrotic neurons were observed throughout the lateral cerebral cortex remote from the impact site. In addition, an intracerebral contusion was present in all rats at the gray-white interface underlying the injured cortical areas. Posttraumatic administration of bFGF significantly reduced the numbers of damaged cortical neuron profiles at several coronal levels and reduced the total number of damaged neurons (696 +/- 148 vs. 1,248 +/- 198, means +/- SEM), p < 0.05, ANOVA). In addition, contusion ares at several coronal levels as well as total contusion volume was significantly reduced (1.13 +/- 0.39 mm(3) vs. 3.18 +/- 0.81 mm(3), p < 0.05). These data demonstrate neuroprotection with intravenous bFGF infusion in the posttraumatic setting.