Excitotoxic cytopathology, progression, and reversibility of thiamine deficiency-induced diencephalic lesions.
ABSTRACT The present study examined the cytopathological changes within diencephalon of a rat model of Wernicke's encephalopathy and determined whether administration of thiamine at various intervals after onset of neurological signs can arrest or reverse the cytopathological process. Electron microscopic examination of the brains from animals sacrificed at four progressively severe stages of pyrithiamine-induced thiamine deficiency (PTD) revealed neurocytopathological changes identical to those that have been described in glutamate-induced excitotoxic lesions. These degenerative changes occurred in gelatinosus (Ge) and anteroventral ventrolateral (AVVL) nuclei at an early symptomatic stage and in the ventroposterolateral (VPL), ventroposteromedial (VPM), and ventrolateral (VL) nuclei at slightly later stages of PTD. Light microscopic evaluation of separate groups of PTD rats administered thiamine at each of the same four neurologic stages and allowed to recover for 1 week demonstrated that thiamine treatment is more effective when administered at earlier stages. However, Ge, AVVL, and VPL nuclei sustain severe damage even when thiamine is administered prior to acute neurologic signs. Furthermore, pathologic changes in the mammillary and several midline intralaminar nuclei begin after thiamine administration and reinstitution of thiamine-replete diet to animals in more severe stages of thiamine deficiency. These and other recent findings suggest that excitotoxic and possibly apoptotic mechanisms may mediate neuronal degeneration in the PTD rat model of Wernicke's encephalopathy, and that multiple factors conducive to excitotoxicity may act in concert to produce this syndrome.
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- "Pyrithiamine induced thiamin deficiency (PTD) in the rat is a well validated experimental model to study the pathophysiology of human Wernicke encephalopathy where the histological lesions generally mirror those seen in the human disorder. If rats are allowed to progress through a severe bout of thiamin deficiency, they develop lesions in the anterior and midline thalamus as well as the mammillary bodies (Zhang et al., 1995; Pfefferbaum et al., 2007). Furthermore, these animals show impaired memory function (Langlais and Savage, 1995) and older animals demonstrate greater susceptibility to brain damage (Pitkin and Savage, 2001). "
ABSTRACT: Although the neuropathology of Korsakoff's syndrome (KS) was first described well over a century ago and the characteristic brain pathology does not pose a diagnostic challenge to pathologists, there is still controversy over the neuroanatomical substrate of the distinctive memory impairment in these patients. Cohort studies of KS suggest a central role for the mammillary bodies and mediodorsal thalamus, and quantitative studies suggest additional damage to the anterior thalamus is required. Rare cases of KS caused by pathologies other than those of nutritional origin provide support for the role of the anterior thalamus and mammillary bodies. Taken together the evidence to date shows that damage to the thalamus and hypothalamus is required, in particular the anterior thalamic nucleus and the medial mammillary nucleus of the hypothalamus. As these nuclei form part of wider memory circuits, damage to the inter-connecting white matter tracts can also result in a similar deficit as direct damage to the nuclei. Although these nuclei and their connections appear to be the primary site of damage, input from other brain regions within the circuits, such as the frontal cortex and hippocampus, or more distant regions, including the cerebellum and amygdala, may have a modulatory role on memory function. Further studies to confirm the precise site(s) and extend of brain damage necessary for the memory impairment of KS are required.Neuropsychology Review 04/2012; 22(2):72-80. DOI:10.1007/s11065-012-9195-0 · 5.40 Impact Factor
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- "There is little evidence for persistent behavioral impairments if rats are treated with thiamine prior to experiencing seizures (Pitkin and Savage 2001). At the early acute stage (EAS) of the PTD model, degenerative changes occur in the gelatinosus and anteroventral ventrolateral nuclei of the thalamus, both of which undergo rapid neuronal loss (see Zhang et al. 1995). Within 1 to 2 h following seizure onset, the brains of PTD-treated rodents exhibit lesions in the ventral and posterior nuclear groups of the thalamus that are characterized by severe neuronal loss and pale neuropil. "
ABSTRACT: Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS.Neuropsychology Review 04/2012; 22(2):195-209. DOI:10.1007/s11065-012-9194-1 · 5.40 Impact Factor
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- "On days 15–17 of treatment, animals developed signs of local tonoclonic movement of the front and hind limbs, and generalized convulsions (seizures). Some studies have implicated glutaminergic excitotoxicity in the formation of PTD-induced seizure-activity (Olney, 1985), but several thalamic nuclei are damaged prior to seizure activity (Zhang et al, 1995). Within 4 hours and 15 minutes of seizure onset, PTD treated animals were given an injection of thiamine hydrochloride (100 mg/kg, i.p., Sigma-Aldrich). "
ABSTRACT: Although the thalamus and/or mammillary bodies are the primary sites of neuropathology in cases of diencephalic amnesia such as Wernicke Korsakoff Syndrome (WKS), there is also functional deactivation of certain cortical regions that contribute to the cognitive dysfunction. Acetylcholine (ACh) is a key neurotransmitter that modulates neural processing within the cortex and between the thalamus and cortex. In the pyrithiamine-induced thiamine deficiency (PTD) rat model of WKS, there are significant reductions in cholinergic innervation and behaviorally stimulated ACh efflux in the frontal (FC) and retrosplenial (RSC) cortices. In the present study, ACh released levels were site-specifically amplified with physostigmine (0.5 μg, 1.0 μg) in the FC and the RSC, which was confirmed with in vivo microdialysis. Although physostigmine sustained high ACh levels in both cortical regions, the effects on spatial memory, assessed by spontaneous alternation, were different as a function of region (FC, RSC) and treatment (PTD, pair-fed [PF]). Higher ACh levels in the FC recovered the rate of alternation in PTD rats as well as reduced arm-reentry perseverative errors. However, higher ACh levels within the FC of PF rats exacerbated arm-reentry perseverative errors without significantly affecting alternation rates. Maintaining high ACh levels in the RSC had no procognitive effects in PTD rats, but rather impaired alternation behavior in PF rats. These results demonstrate that diverse cortical regions respond differently to intensified ACh levels-and the effects are dependent on thalamic pathology. Thus, pharmacotherapeutics aimed at enhancing cognitive functions must account for the unique features of cortical ACh stimulation and the connective circuitry with the thalamus.Behavioral Neuroscience 04/2012; 126(2):226-36. DOI:10.1037/a0027257 · 3.25 Impact Factor