The effect of subchronic supplementation with folic acid and l-arginine on homocysteine-induced seizures.

The aim of the present study was to examine the effect of subchronic co-administration of folic acid (F) and l-arginine (A) on behavioural and electroencephalographic (EEG) characteristics of dl homocysteine thiolactone (H) induced seizures in adult rats. The activity of membrane ATPases in different brain regions were also investigated. Rats were treated with F, A, or vehicle for 15 days (regimen: F 5 mg/kg + A 500 mg/kg (F5A500); F 10 mg/kg + A 300 mg/kg (F10A300)). Seizures were elicited by convulsive dose of H (H, F5A500H, F10A300H) Subchronic supplementation with F and A did not affect seizure incidence, number of seizure episodes, and severity in F5A500H and F10A300H groups vs. H group. However, a tendency to increase latency and decrease the number of seizure episodes was noticed in the F10A300H group. EEG mean spectral power densities during ictal periods were significantly lower in F10A300H vs. H group. The activity of Na+/K+-ATPase and Mg2+-ATPase was significantly increased in almost all examined structures in rats treated with F and A. We can conclude that subchronic supplementation with folic acid and l-arginine has an antiepileptic effect in dl homocysteine thiolactone induced epilepsy.

[Potentiation of metaphit-induced audiogenic epilepsy with N-methyl-D-aspartate in rats]. / Potencijacija audiogene metafitske epilepsije en-metil-de-aspartatom kod pacova.

INTRODUCTION: Audiogenic seizures (AGS) are induced by high intensity sound stimulation in genetically susceptible rats or in animals subjected to chemical or electrical manipulation. Epileptic seizure may result from an impaired balance between excitation and inhibition in the CNS. The effect of NMDA (N-methyl-D-aspartic acid) on metaphit 1-(1(3-isothiocyanatophenyl-ciclohexyl)-piperidine) induced audiogenic seizures was evaluated in rats. METHODS: Male Wistar albino rats were divided into 4 groups: 1) saline; 2) metaphit (10 mg/kg); 3) metaphit + NMDA; 4) NMDA (70 mg/kg). Animals were injected with metaphit intraperitoneally (i.p.) and exposed to sound stimulation (100 +/- 3 dB, 60 s) at hourly intervals. The incidence and severity (running, clonus and tonus) of seizures were analyzed. NMDA alone was administered i.p. to 6 rats. In group metaphit + NMDA only animals which did not exhibit any seizure during 8 hours were injected with NMDA i.p. after the 8th audiogenic testing. For electroencephalograph (EEG) recordings three gold-plated screws were used. Convulsive behaviour was assessed by incidence of motor seizure and by seizure severity grade, determined by use of a descriptive rating scale with range of 0-3; 0-no response; 1-wild running only; 2-wild running followed by clonic seizures of all four limbs with body rollover; 3-wild running progressing to generalized clonic convulsions and then a tonic extension of the fore and hind limbs and tail. Sound onset, seizure events, and sound offset, along with the animals behaviour (convulsive or other) were recorded as the correlates to the respective EEG responses. RESULTS: In most animals the administration of metaphit (10 mg/kg) resulted in electrographic abnormalities, elicited epileptiform activity in the form of spikes, polyspikes and spikewave complexes (Fig. 1.). Maximum incidence and severity of metaphit convulsions occurred 8 h after the injection (9/12, 75%) (Fig. 2, 3.), then abated gradually and disappeared 30 h later. NMDA (70 mg/kg) alone induced no seizure response but isolated spiking activity, and sporadic slow-wave complexes were recorded (Fig. 4). NMDA induced stereotyped behaviour in the form of asymmetric posture, loss of righting reflex and tonic hindlimb extension, which lasted for 60-90 min. Subconvulsive dose of NMDA potentiated the metaphit-induced audiogenic seizures in rats. Two hours after NMDA administration 3 of 17 metaphit-treated rats convulsed, which in 8 previous testings never displayed seizures. Maximum incidence was 8 of 17 (53%), 5-6 h after NMDA administration and seizures lasted for 9 hours. DISCUSSION: Several authors reported that metaphit dose of 10 mg/kg accompanied by some REM sleep deprivation (REM-D) procedures [4], or subconvulsive doses of NMDA [25] provoked seizures of higher intensity and incidence. Metaphit treatment (10 mg/kg) followed 24 h later by NMDA dose of 50 mg/kg provoked no spontaneous convulsions, while metaphit in combination with a higher NMDA dose of 70 mg/kg resulted in spontaneous and AGS-induced seizures only in one time point [25]. It was found that the incidence and severity of convulsive responses were highest 8-12 h after metaphit injection (10 mg/kg) [23, 24]. Although about 8 h after metaphit administration the power spectra increased and were more intense in the period of sound onset and seizure events. CONCLUSION: The results of the present study strongly suggest that treatment of adult rats with the combination of metaphit and NMDA in the doses employed here followed by AGS provides a suitable animal model for examinations of epileptic seizures.

APH, an N-methyl-D-aspartate receptor antagonist, blocks the metaphit-induced audiogenic seizures in rats.

The effect of the competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, (+/-)2-amino-7-phosphonoheptanoic acid (APH) on electrocorticographic (ECoG) activity and behavior was studied in the model of epilepsy induced by systemic application of metaphit (1-(1-(3-isothiocyanatophenyl)-cyclohexyl)-piperidine). Male Wistar rats were injected with metaphit intraperitoneally (10 mg/kg, i.p.), and exposed to intense audio stimulation (electric bell generating 100 +/- 3 dB at animal level for 60 s) 1 h after administration and at 1-h intervals thereafter. ECoG tracings showed appearance of paroxysmal activity in form of spikes, spike-wave complexes and ECoG seizures. Audiogenic seizures consisted of wild running followed by clonic and tonic convulsions. Each behavioral seizure response had a characteristic ECoG correlate. The incidence and severity of seizures increased with time, reaching a peak 8-12 h after metaphit administration, and then gradually decreased until 31 h, when no animal responded to sound stimulation. APH was injected intracerebroventricularly (0.005, 0.01, 0.02, 0.03 and 0.05 mumol icv in 5 microL of sterile saline) after the 8th hour of audiogenic testing (AGS). APH inhibited seizures in a dose-dependent manner. The minimum dose which blocked seizures in all animals was 0.03 mumol. However, ECoG signs of seizure susceptibility were not suppressed by APH. After varying periods of time, behavioral seizures reappeared. It seems that APH blocks epileptiform propagation, but has less influence on the epileptogenic activity caused by metaphit.

[Eponyms and epilepsy (history of Eastern civilizations)]. / Eponimi i epilepsija (istorijat istocnih civilizacija).

The history of eponyms for epilepsy in the lands of the Eastern globe present the portrait of the attitudes of both the laymen and skilled people towards the disease and patient, as well as to the Nature itself. As opposed to the West which during the Middle ages changed its concepts of epilepsy as the organic brain disease for the sublime 'alchemic' position, the people of the East were more prone to consider from the beginning of their civilization till the XIX century that epilepsy is the consequence of the evanescent spiritual and extracorporal forces which by themselves were out of their reach. As compared to the western civilization, the historical resources are, often as a consequence of a linguistic barriers, more scarce-as consequently is the number of eponyms, but are nevertheless picturesque. The medical science from Babylonian period presumed that epileptic manifestations are the consequence of the demonic or ill spiritual actions. There existed an attitude that at the beginning of an epileptic attack the patient was possessed by a demon (the Akkadic, i.e., Babylonian verb "sibtu" denoting epilepsy, had the meaning "to seize" or "to be obsessed"); at the end of the clonic phase the demon departed from the body. Different demons were responsible for different forms of epilepsy such as nocturnal and children epilepsy, absence epilepsy and pure convulsions, simple and complex automatisms, and gelastic epilepsy. Thus, the doctors from the period of Babylon aside from making primordial classification of epilepsies, knew about their clinical picture (prodromal symptoms and aura, Jackson's epilepsy. Todd's paralysis), postictal phenomena and intericatl emotional instability; provocative factors were also known (sleep deprivation, emotions, as well as alcohol, albeit in a negative sense-as a cure for epilepsy). There is no doubt than in the period of Babylon the clinical picture of serial fits and its progress to status epilepticus were clearly recognized and considered as life threatening events. Persian history of epilepsy, except from the 6th century Zoroastrian "Avesta" document, lacks the written or spoken medical heritage untill the 7th century A.D. and the Arabic conquest of the entire Moslem world. On the other hand, Islamic medicine should be freed from the simple prejudice that the Moslem authors were only the translators of Greek medicine; contrary to such a view, their work contains a high degree of individuality. Although Mohammed introduced a lot of novelty into medicine, Khoran and the Sayings do not explicitly refer to epilepsy. Of importance is to notice that Moslem medicine did not have demons in the "repertoire" of direct causes of epilepsy. The causes and the cures of epilepsy were more magic-mystical and occult in nature, which is reminiscent of the European, as well as Serbian Middle age attitudes. Avicenna recognized difference between children and adult epilepsy. He considered insomnia and afternoon siesta as well as intensive sounds and light to be a provocative factors, whereby we see that at least empirically he knew of sleep (deprivation), startle and reflex epilepsy. The XIII century invasion of Mongols brought about the recession in Moslem Medicine; it recovered only in the XVIII century under the strong influence of European medicine handed over to us through Jewish doctors of various nationalities. The story of the China history of epilepsy has its debut approximately in the 8th century B. C. Medical texts from this period name epilepsy "Dian" and "Xian" which meant "the falling sickness" and "convulsions", respectively. Chinese medical terminology often interchangeably used the words "mania", "madness" and "psychosis" for "epilepsy" which, aside from a prominent language barrier, brings additional confusion. Although Chinese documents gave the first description of the grand mal epileptic attack already in the 8th century B. C. (ABSTRACT TRUNCATED)

[Epilepsy, eponyms and patron saints (history of Western civilization)]. / Epilepsija, eponimi i pokrovitelji (istorijat zapadnih civilizacija).

From a historic point of view, epilepsy and its eponyms were in an ontogenetic symbiosis throughout their history. Epilepsy is a disease with a history of eponyms presenting the frame of mind of both streetwise as well as skilled "authors" about its origin and nature. From ancient times the names for epilepsy, archetypal Hippocratic disease, just as rich in number as varied in their implication, reflected the local folkways of thinking. In this article we briefly presented more than 50 eponyms and patrons of epilepsy. As the source of information we used both the apocryphal, canonical and hagiographic as well as heretic literature, legends and iconography from the Middle Ages of domestic and foreign origin. Pre- and post-Hippocratic era, apart from stemming from the oldest written medical sources, point to the position that the disease had organic origin located in the brain. The period of Rome adopted the attitudes set by Galen which remained en vogue throughout the emerging Middle Ages and Renaissance. These eras generated new eponyms which reflected a downfall in the manor, stating that the disease is the consequence of supernatural forces. In the "Age of darkness" eponyms for epilepsy reflected more the relation of men to the Nature than to the disease or a sick man; this is evidenced through the generation of number of patrons for the disease. The most famous patron of patients with epilepsy was St. Valentine (after conversion from pagandom he died in Rome as a martyr, c. 270). He was allotted a patronage either due to the phonic resemblance of his name with the (past participle of the) verb "fallen"-as Martin Luther claimed, or due to a cure of epilepsy of the son of a Roman rhetor who built for him a chapel in which he continued to cure the sick. The emergence of a flamboyant personality of Paracelsus on the historic scene of the XVI century represents a less successful attempt to revoke the way of thinking set by the old Greek doctors; however, it brought about the precipitous decay of attitudes that started with Romans and inaugurated the way of thinking characteristic of Renaissance and the ages thereafter. Serbian literature of the Middle Age was strongly impacted by influences that fanned from Italy (Salerno) and south France (Montpellier), reflecting the attitudes of medical schools and universities prevailing at that time Europe. The name [symbol: see text] from Hilandar Medical Codex No 517 (XV-XVI century) is obviously taken from Byzantine medicine, which was founded on the works of Hippocrates, Galen and Dioscurides. It came down to us through the Serbian folk Byzantine codices named "latrosophia of Hilandar", preserved mostly from the author Michail Pselos (XI century). On the other hand, the name [symbol: see text] or morbus magnus, reflects its Roman origin. The name [symbol: see text] meaning fainting, loss of consciousness or syncope, stems from the same source. The name [symbol: see text] designated epileptic disease in Serbian monks, monasteries probably being the only niche where epileptics could find refuge. Children's epilepsy or convulsions are expressed as [symbol: see text] No mention is found of epileptic status except for the notion [symbol: see text] meaning "to be without consciousness for a longer period of time'; it does not, however, refer directly to epilepsy or convulsions. It is worthy noting that already in the XIV century Serbs had their medical literature translated to their own language, and were the only one of all Slavic peoples that did so. Nevertheless, both apocryphal and canonical, as well as consecrated medicine were based on magic, astrology and occultism. The magic formulas used in Middle Age Serbia for the cure of epileptics as well as sick in general, were basically irrational; still, as a trace of its descension they contained unintelligible words of the eastern origin (Greek, Persian or Jewish). (ABSTRACT TRUNCATED)

Potentiation of metaphit-induced audiogenic seizures by REM sleep deprivation in rats.

The possibility that REM sleep deprivation (REMD) induced increased susceptibility of rats to the convulsive effects of metaphit was investigated. Metaphit-induced audiogenic seizures were studied in three groups of animals: 1) caged controls; 2) large platform animals; and 3) small platform, REMD animals. After 48 h of confinement to their environments the rats from all three groups were injected with metaphit (10 mg kg-1, IP) and the procedures continued for the next 24 h. Immediately after removal from platforms and at 3-h intervals thereafter all rats were individually subjected to intense sound stimulation. Convulsive responses were recorded and analyzed with respect to incidence, intensity, and duration. The REMD rats were found to be more sensitive to the convulsive effects of metaphit compared to nondeprived rats. This was manifested in significantly shorter latencies to seizures, and significantly higher incidence, severity, and duration of seizures, especially of the most severe seizure component-tonic extensor convulsion. Inducing rats to convulse while they were being REM sleep deprived eliminated the REM sleep rebound observed in REMD rats that did not convulse. The occurrence of spontaneous EEG seizures during the undisturbed recovery period reduced REM sleep rebound. The results demonstrate a reciprocal relation between seizure behavior and REM sleep.

Metaphit-induced audiogenic seizure and its inhibition by MK-801: electroencephalographic and behavioral characterization.

Adult male Wistar rats were subjected to intense sound stimulation from an electric bell (100 dB and 12 KHz for 60 s) after a single intraperitoneal (i.p. 50 mg/kg) injection of metaphit [1-(1-/3 isothiocyanatophenyl-cyclohexyl) piperidine]. EEG recordings demonstrated appearance of paroxysmal activity and spike-wave complexes from cortical electrodes, with frequency and amplitude increasing with time. Metaphit-induced audiogenic seizures in the rats were tested 24 h after metaphit administration. The seizures consisted of wild running followed by clonic and tonic convulsions, and the seizure pattern could be elicited at hourly intervals for the next 24 h in all tested animals. Forty-eight hours after metaphit administration, susceptibility to sound stimulation began to decrease gradually. The first component of seizure response to disappear was tonic extension, followed by disappearance of clonic convulsion; the last component to disappear was running behavior. Each behavioral seizure response had a characteristic EEG correlate. After approximately 50 h, no animal responded to sound stimulation. The noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, MK-801 [5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate] was evaluated as an anticonvulsant against metaphit-induced audiogenic seizures in two experiments. In the first experiment, MK-801 was administered in a single dose of 0.5 mg/kg i.p. 23.5 h after metaphit injection and 30 min before sound stimulation, which completely blocked both the EEG and the behavioral response to sound stimulation for 37 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Electroencephalographic characteristics of audiogenic seizures induced in metaphit-treated small rodents.

Adult male mice, rats, and guinea pigs were subjected to intense sound stimulation of an electric bell (100 dB, 12 kHz for 60 s) after a single intraperitoneal (i.p.) injection of metaphit (1-(1-(3 isothiocyanatophenyl)-cyclohexyl)piperidine) (50 mg/kg). When the animals were tested 24 h after administration of metaphit, audiogenic seizures were observed. None of the control saline-injected animals had convulsions. EEG recordings demonstrated the appearance of paroxysmal activity and spike-wave complexes in the trace from cortical and hippocampal electrodes, with frequency and amplitude increasing with time. Behaviorally, myoclonic jerks of facial muscles, ears, and neck appeared, but no correlation was noted between EEG and the motor phenomena. Auditory stimulation was necessary to elicit the full-blown sequence of seizure responses consisting of wild running followed by clonic and then tonic extension. At the time of seizures, repetitive high-amplitude spikes and waves appeared in the EEG, followed by profound EEG and behavioral depression. None of the animals died during or immediately after seizures. The seizure response to sound stimulation of mice, rats, and guinea pigs was phenomenologically similar, with minor differences in quantitative pattern of convulsive components, which suggests that all three animal species share the common property of extreme susceptibility to audiogenic stimulation caused by metaphit administration.