dizocilpine-maleate and Thiamine-Deficiency

Thiamine or vitamin B(1), an essential nutrient absorbed from the diet, is involved in vital brain metabolic and cellular functions, including carbohydrate metabolism and neurotransmitter production. Diencephalic regions and, in particular, the cerebellum demonstrate lesions in cases of prolonged thiamine deficiency, such as that observed in alcohol-dependent individuals or in patients with cancer or AIDS. The purpose of this review is to demonstrate recent evidence of cerebellar dysfunction resulting from thiamine deficiency and to assemble theories as to why the cerebellum may be sensitive to this type of insult. A brief outline on cerebellar structure and function, as well as a short discussion on thiamine and thiamine deficiency are provided before detailing the conditions and mechanisms underlying thiamine deficiency-induced cerebellar dysfunction. Although much is known regarding cell loss from a lack of thiamine, further work is still required to identify the sequelae of events leading to the susceptibility of the cerebellum to injury stemming from a thiamine deficient diet or impaired thiamine utilization.

Topics: Acetaldehyde; Animals; Cerebellum; Disease Susceptibility; Dizocilpine Maleate; Drug Interactions; Gait Ataxia; Humans; Neurons; Pyrithiamine; Thiamine Deficiency

The relationship of thiamine deficiency to Wernicke's encephalopathy has been well established. The biochemical bases and physiologic mechanisms responsible for the pathologic changes and their selective distribution within the brain remain controversial. The present paper reviews recent biochemical, histopathological and pharmacological evidence of a glutamate-mediated excitotoxic mechanism of neuronal loss in pyrithiamine-induced thiamine deficiency (PTD), a rat model of Wernicke's encephalopathy. A mechanistic model involving the unique combination of thiamine deficiency-induced impairment of energy metabolism, increased release of histamine, and multidirectional glutamate inputs is presented to explain the selective vulnerability of thalamic nuclei to excitotoxic lesions in the PTD model.

Topics: Animals; Brain Damage, Chronic; Diencephalon; Disease Models, Animal; Dizocilpine Maleate; Energy Metabolism; Histamine; Magnesium; Mammillary Bodies; Rats; Thalamus; Thiamine Deficiency; Wernicke Encephalopathy

Thiamine/vitamin B1 deficiency can lead to behavioral changes and neurotoxicity in humans. This may due in part to vascular damage, neuroinflammation and neuronal degeneration in the diencephalon, which is seen in animal models of pyrithiamine-enhanced thiamine deficiency. However, the time course of the progression of these changes in the animal models has been poorly characterized. Therefore, in this study, the progression of: 1) activated microglial association with vasculature; 2) neurodegeneration; and 3) any vascular leakage in the forebrain during the progress of thiamine deficiency were determined. A thiamine deficient diet along with 0.25 mg/kg/d of pyrithiamine was used as the mouse model. Vasculature was identified with Cd31 and microglia with Cd11b and Iba1 immunoreactivity. Neurodegeneration was determined by FJc labeling. The first sign of activated microglia within the thalamic nuclei were detected after 8 d of thiamine deficiency, and by 9 d activated microglia associated primarily with vasculature were clearly present but only in thalamus. At the 8 d time point neurodegeneration was not present in thalamus. However at 9 d, the first signs of neurodegeneration (FJc + neurons) were seen in most animals. Over 80% of the microglia were activated at 10 d but almost exclusively in the thalamus and the number of degenerating neurons was less than 10% of the activated microglia. At 10 d, there were sporadic minor changes in IgG presence in thalamus indicating minor vascular leakage. Dizocilpine (0.2-0.4 mg/kg) or phenobarbital (10-20 mg/kg) was administered to groups of mice from day 8 through day 10 to block neurodegeneration but neither did. In summary, activated microglia start to surround vasculature 1-2 d prior to the start of neurodegeneration. This response may be a means of controlling or repairing vascular damage and leakage. Glutamate excitotoxicity and vascular leakage likely only play a minor role in the early neurodegeneration resulting from thiamine deficiency. However, failure of dysfunctional vasculature endothelium to supply sufficient nutrients to neurons could be contributing to the neurodegeneration.

Topics: Animals; Blood Vessels; Calcium-Binding Proteins; CD11b Antigen; Diet; Dizocilpine Maleate; Female; Mice; Microfilament Proteins; Microglia; Nerve Degeneration; Phenobarbital; Pyrithiamine; Thalamus; Thiamine Deficiency; Time Factors

In both acute ethanol intoxication and in thiamin deficient glucose metabolism, previous studies have detected blood-brain barrier (BBB) and/or blood-CSF-barrier (BCSFB) impairment but were unable to assess their significance in relation to other changes in the brain.. Contrast-enhanced, magnetic resonance imaging (MRI) was used to detect and time any impairment of the BBB or BCSFB in rats given an acute ethanol load or in rats made thiamin deficient to the point of mild ataxia and then given an acute glucose load.. The BCSFB at the choroid plexus (CP) was impaired within 10 minutes by either (i) a single i.p. dose of glucose in thiamin-deficiency, an effect that was attenuated by prior MK801 and preceded the published onset of exacerbation of motor incoordination and elevation of brain glutamate derivatives; or (ii) a single i.p. dose of ethanol in thiamin-sufficiency, an effect that was proportional to the blood alcohol concentration and preceded the published onset of signs of intoxication. In contrast to the BCSFB, the BBB remained intact throughout the 90 minutes period of these experiments.. In both ethanol intoxication and thiamin-deficient glucose metabolism, BCSFB impairment exposes the CSF and hence the brain extracellular fluid to neuroactive substances from the blood. CP impairment is the earliest detected event in both these animal models; and explains the paraventricular location of WE neuropathology and why WE is associated with, but not dependent on, alcoholism.

Topics: Alcoholic Intoxication; Animals; Blood-Brain Barrier; Central Nervous System Depressants; Choroid Plexus; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ethanol; Female; Glucose; Magnetic Resonance Imaging; Neuroprotective Agents; Rats; Rats, Wistar; Thiamine Deficiency; Wernicke Encephalopathy

Pyrithiamine-induced thiamine deficiency (PTD), which has been used as a model of Wernicke-Korsakoff syndrome (WKS), produces a range of neuropathological and behavioral abnormalities in rodents. The extent of the diencephalic damage produced by this treatment varies from moderate to extreme cell loss. The magnitude of working memory impairment tends to correlate with the degree of neuropathology. In this study a PTD protocol that produces moderate thalamic pathology was used to gain further insight into the neurobehavioral consequences of thiamine deficiency. Towards this end, two distinct manipulations were conducted. First, the differential outcomes procedure (DOP), which correlates specific reinforcers with specific to-be-remembered events, was applied to an operant version of matching-to-position (MTP). This behavioral manipulation was conducted to determine if the DOP would improve memory performance in PTD-treated rats, demonstrating some intact cognitive functions. Additionally, to assess the functional integrity of the cholinergic and glutamatergic systems, normal and PTD-treated rats were administered i.p. injections of scopolamine and MK-801. It was found that the DOP enhanced memory, but not acquisition performance, in both normal and PTD-treated rats. Furthermore, when administered scopolamine, but not MK-801, rats trained with the DOP continued to outperform rats trained with a non-differential outcomes procedure (NOP). However, PTD-treated rats, regardless of training procedure (DOP, NOP), were more disrupted by the 'amnestic' effects of both scopolamine and MK-801. The differential sensitivity of treatment groups to the amnestic effects of scopolamine and MK-801 reveals insights into the neurochemical correlates of memory processes and WKS.

Topics: Acute Disease; Amnesia; Analysis of Variance; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Korsakoff Syndrome; Male; Memory, Short-Term; Pyrithiamine; Rats; Rats, Sprague-Dawley; Reaction Time; Scopolamine; Thalamus; Thiamine Deficiency

The goal of the studies described was to evaluate the role of NMDA receptor-mediated glutamate excitotoxicity in the pathogenesis of selective neuronal loss due to thiamine deficiency. Administration of the central thiamine antagonist pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including ataxia and loss of righting reflex followed by convulsions. Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the ventral posterior medial thalamic nucleus. However, in vivo cerebral microdialysis at preconvulsive stages did not demonstrate significant increases of extracellular glutamate in this region and pretreatment with the NMDA receptor antagonist MK801 (1 mg/ kg/12 h, i.p.) did not afford significant neuroprotection. Following the onset of convulsions, microdialysate glutamate concentrations were increased fivefold (P > 0.05) and MK801 treatment resulted in significant attenuation of neuronal loss in some thalamic nuclei. A comparable degree of neuroprotection was afforded by pretreatment with an anticonvulsant dose of diazepam (10 mg/kg/12 h, i.p.) a compound whose action is not NMDA receptor mediated. These findings suggest that NMDA receptor-mediated excitotoxicity is not responsible for early selective neuronal loss in this model of thiamine deficiency encephalopathy and that the neuroprotective effect of MK801 at later stages are at least in part a consequence of its anticonvulsant properties.

Topics: Animals; Anticonvulsants; Behavior, Animal; Cell Count; Cell Death; Diazepam; Dizocilpine Maleate; Glutamic Acid; Male; Microdialysis; Neurons; Neuroprotective Agents; Neurotoxins; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Thiamine Deficiency; Wernicke Encephalopathy

Synaptic plasma membranes were prepared from four cerebrocortical areas from six male Angora goats made chronically thiamine deficient (TD) by the administration of AmproliumTM (600-900 mg/kg daily for 38-44 d). Four male controls were matched for age (27-30 mo). Four different radioligands were used to characterise GABAA and Glu-RNMDA receptor binding sites. There were marked, localised and contrasting changes in motor cortex, with an increase in GABAA and a decrease in Glu-RNMDA binding site densities. Less clearcut changes of a similar nature were seen in visual cortex. There was no variation in the parameters of GABA-activated [3H]diazepam binding between cortical areas in control goats, but there was a reduction in the maximal response to GABA in all areas in TD goats. There were regional variations in glutamate-activated [3H]MK-801 binding in control goat brain, and a non-selectively reduced maximal response in TD. Alterations in these indices of GABA- and glutamate-mediated neurotransmission may underlie the neurological signs of acute thiamine deficiency in these animals.

Topics: Alcoholism; Amprolium; Animals; Brain Chemistry; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Flunitrazepam; GABA Agonists; GABA Modulators; gamma-Aminobutyric Acid; Goats; In Vitro Techniques; Male; Muscimol; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Synaptic Membranes; Synaptosomes; Thiamine Deficiency

The current study measured extracellular fluid (ECF) levels of excitatory amino acids before and during the onset of thiamine deficiency-induced pathologic lesions. Male Sprague-Dawley rats were treated with daily pyrithiamine (0.25 mg/kg i.p.) and a thiamine-deficient diet (PTD). Microdialysates were simultaneously collected from probes inserted acutely via guide cannulae into right paracentral and ventrolateral nuclei of thalamus and left hippocampus of PTD and pair-fed controls. Hourly samples were collected from unanesthetized and freely moving animals. Basal levels obtained at a prelesion stage (day 12 of PTD treatment) were unchanged from levels in pair-fed controls. In samples collected 4-5 h after onset of seizures (day 14 of PTD), the levels of glutamate were elevated an average 640% of basal levels in medial thalamus and 200% in hippocampus. Glutamine levels declined, taurine and glycine were elevated, and aspartate, GABA, and alanine were unchanged during this period. Within 7 h after seizure onset glutamine was undetectable in both areas, whereas glutamate had declined to approximately 200% in thalamus and 70% in hippocampus. No significant change in glutamate, aspartate, or other amino acids was observed in dialysates collected from probes located in undamaged dorsal-lateral regions of thalamus. Number of neurons within ventrolateral nucleus of thalamus was significantly greater in PTD animals in which the probe was dialyzed compared with nondialyzed, suggesting that removal of excitatory amino acids was protective. No significant pathologic damage was evident in hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Dizocilpine Maleate; Extracellular Space; Hippocampus; Male; Microdialysis; Pyrithiamine; Rats; Rats, Sprague-Dawley; Reference Values; Seizures; Thalamus; Thiamine; Thiamine Deficiency; Time Factors

Rats were trained on a spatial delayed-nonmatching-to-sample (DNMTS) task and assigned by block randomization to one of four treatments: pyrithiamine-induced thiamine deficiency (PTD), PTD with administration of MK-801 after 12 days, control with MK-801 treatment, and control without MK-801. After 15 days of treatment followed by 21 days of recovery, the PTD rats showed significant deficits for DNMTS accuracy at retention intervals (RI) that ranged from 3.0 s to 15.0 s, the RIs that produced 75% accuracy on DNMTS in staircase training, and the rate at which a novel radial arm maze task was learned. The PTD-treated rats had consistent lesions in the thalamus and the mammillary bodies. MK-801 protected rats from both behavioral deficits and brain lesions (assessed quantitatively and qualitatively) that were produced by the PTD treatment.

Topics: Alcohol Amnestic Disorder; Animals; Appetitive Behavior; Brain Mapping; Discrimination Learning; Dizocilpine Maleate; Male; Mental Recall; Orientation; Pyrithiamine; Rats; Reaction Time; Receptors, N-Methyl-D-Aspartate; Retention, Psychology; Thalamus; Thiamine Deficiency; Wernicke Encephalopathy

An acute bout of pyrithiamine-induced thiamine deficiency (PTD) produces pathologic lesions within thalamus, mammillary body, and periventricular regions of rat brain. The biological bases for these pathologic changes and their selective distribution within the brain are unclear. The type of tissue damage observed within the thalamus of PTD rats closely resembles that observed following anoxic-ischemic insults and suggests the involvement of excitotoxic amino acids in its pathogenesis. The effects of the N-methyl-D-aspartate receptor antagonist MK-801 (3 mg/kg, i. p.) on brain lesions and amino acid changes have been assessed in rats killed during the late acute stages of PTD. A marked loss of neurons within midline intralaminar nuclei and the posterior nuclear group of the thalamus were observed in the early acute stage of PTD treatment. In the late acute stage, these changes were present throughout the entire thalamus and extended caudally to the periacqueductal gray and mesencephalic tegmentum. Hemorrhagic lesions were observed only in the late acute group and were the primary lesion within the mammillary body and medial and lateral geniculates. No pathologic changes were observed in hippocampus, amygdala, and cortex. MK-801 administered during the late stages resulted in a marked attenuation of necrotic damage to thalamus and periacqueductal gray and a reduction in the number and size of hemorrhagic lesions. Significant reductions of aspartate and glutamate and increases of glycine were observed in 5 regions of thalamus, the hippocampus, hypothalamus, and mammillary bodies of both the early and late acute PTD groups. Levels of GABA and taurine in caudal areas were significantly elevated in the early acute stage but were unchanged from controls in the late acute group. These amino acid changes were reduced in the MK-801 treated late acute group. These observations suggest that NMDA receptors are involved the pathogenesis of PTD-induced brain lesions and that nuclei of the intralaminar and posterior nuclear groups are most vulnerable to PTD effects.

Topics: Amino Acids; Animals; Behavior, Animal; Brain; Dibenzocycloheptenes; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Pyridinium Compounds; Pyrithiamine; Rats; Rats, Inbred Strains; Thiamine Deficiency; Time Factors