Article

In vivo imaging of dopamine receptors in a model of temporal lobe epilepsy

Department of Nuclear Medicine, University of Mainz, Mainz, Germany.
Epilepsia (Impact Factor: 4.58). 08/2009; 51(3):415-22. DOI: 10.1111/j.1528-1167.2009.02272.x
Source: PubMed

ABSTRACT Alterations in dopamine neurotransmission in animal models of epilepsies have been frequently demonstrated using invasive neuroscience or ex vivo techniques. We aimed to test whether corresponding alterations could be detected by noninvasive in vivo brain imaging with positron emission tomography (PET) in the chronic phase of the rat pilocarpine model of temporal lobe epilepsy.
Six pilocarpine-treated Wistar rats exhibiting spontaneous recurrent seizures and nine control rats were studied with PET using [(18)F]-fallypride, a high-affinity dopamine D(2/3) receptor ligand. Parametric images of [(18)F]-fallypride specific binding were calculated using a reference tissue method, and the two groups were contrasted by whole-brain voxel-based analysis implemented in statistical parametric mapping (SPM5).
Dopamine D(2/3) receptor availability was 27% lower in the bilateral anterior caudate-putamen of pilocarpine-treated rats as compared to controls (p < 0.05), but binding was unaffected in other striatal or extrastriatal regions.
The finding of substantially reduced availability of dopamine D(2/3) receptors in the anterior caudate-putamen of rats during the chronic phase of the pilocarpine model is in agreement with results of invasive (microinjection, microdialysis) animal studies that have revealed increased dopamine tonus and a D(2/3) receptor-mediated anticonvulsant action of dopamine in the anterior segment of the rat striatum. The present PET approach could be prospectively applied for monitoring dopamine receptor changes longitudinally, that is, at different phases of the epileptogenic process, and opens perspectives for testing dopaminergic agents as potential antiepileptogenic drugs.

Download full-text

Full-text

Available from: Erwan Dupont, Sep 22, 2014
0 Followers
 · 
142 Views
  • Source
    • "Unlike postmortem analyses, in which observations are limited to specific time points following insults, in vivo studies can assess the evolution and resolution of brain processes over time. Several in vivo imaging studies have established the utility of the pilocarpine model for investigating the epileptogenesis of TLE (van Eijsden et al., 2004; Niessen et al., 2005; Kuo et al., 2008; Yakushev et al., 2010). Therefore, 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) can be used to monitor glucose metabolism in vivo, showing that interictal hypometabolism may be associated with the epileptic network. "
    [Show abstract] [Hide abstract]
    ABSTRACT:   The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. (18) F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and proton magnetic resonance spectroscopy ((1) H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium-pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS).   PET and MRS were performed at baseline, and during the acute, subacute, silent, and chronic periods after lithium-pilocarpine induced status epilepticus (SE). Sequential changes in glucose metabolism on (18) F-FDG PET using SPM2 and the ratios of percent injected dose per gram (%ID)/g of regions of interest (ROIs) in the bilateral amygdala, hippocampus, basal ganglia with the thalamus, cortex, and hypothalamus normalized to the pons were determined. Voxels of interest (VOIs) on (1) H MRS were obtained at the right hippocampus and the basal ganglia. NAA/Cr levels and Cho/Cr at various time points were compared to baseline values.   Of 81 male Sprague-Dawley rats, 30 progressed to SRS. (18) F-FDG PET showed widespread global hypometabolism during the acute period, returning to baseline level during the subacute period. Glucose metabolism, however, declined in part of the hippocampus during the silent period, with the hypometabolic area progressively expanding to the entire limbic area during the chronic period. (1) H MRS showed that the NAA/Cr levels in the hippocampus and basal ganglia were reduced during the acute period and were not restored subsequently from the subacute to the chronic period without any significant change in the Cho/Cr ratio throughout the entire experiment.   Serial metabolic and biochemical changes in the lithium-pilocarpine model of epilepsy indirectly represent the process of human epileptogenesis. Following initial irreversible neural damage by SE, global glucose metabolism transiently recovered during the subacute period without neuronal recovery. Progressive glucose hypometabolism in the limbic area during the silent and chronic periods may reflect the important role of the hippocampus in the formation of ongoing epileptic network during epileptogenesis.
    Epilepsia 03/2012; 53(5):860-9. DOI:10.1111/j.1528-1167.2012.03432.x · 4.58 Impact Factor
  • Source
    • "PET can effectively monitor the area that is responsible from epilepsy comas (Wagner, 1995). A research group (Yakushev et al. 2010) tried to image the brain of rat having epilepsy by PET. [ 18 F]-fallypride was used as a PET tracer which is highly specific to dopamine D2/3 receptor ligand on six rats treated with pilocarpine exhibiting spontaneous recurrent seizures and nine control . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Among different imaging modalities, Positron Emission Tomography (PET) gained importance in routine hospital practice depending on ability to diagnose diseases in early stages and tracing of therapy by obtaining metabolic information. The combination of PET with Computed Tomography (CT) forms hybrid imaging modality that gives chance to obtain better images having higher resolution by fusing both functional and anatomical images in the same imaging modality at the same time. Therefore, better contrast agents are essentially needed. The advance in research about developing drug delivery systems as specific nanosized targeted systems gained an additional importance for obtaining better diagnosis and therapy of different diseases. Liposomes appear to be more attractive drug delivery systems in delivering either drugs or imaging ligands to target tissue or organ of diseases with higher accumulation by producing in nano-scale, long circulating by stealth effect and specific targeting by modifying with specific ligands or markers. The combination of positron emitting radionuclides with liposomes are commonly in research level nowadays and there is no commercially available liposome formulation for PET imaging. However by conjugating positron emitter radionuclide with liposomes can form promising diagnostic agents for improved diagnosis and following up treatments by increasing image signal/contrast in the target tissue in lower concentrations by specific targeting as the most important advantage of liposomes. More accurate and earlier diagnosis of several diseases can be obtained even in molecular level with the use of stable and effectively radiolabeled molecular target specific nano sized liposomes with longer half-lived positron emitting radionuclides.
    Drug Delivery 01/2012; 19(1):68-80. DOI:10.3109/10717544.2011.635721 · 2.20 Impact Factor
  • Source
    • "This result may be consistent with a recent study reporting that pilocarpine-injected rats developed spontaneous recurrent seizures (SRS), even in the absence of initial SE, after a long latency period (Navarro Mora et al., 2009). In a separate report, the availability of the dopamine D 2/3 receptor in the anterior striatum was 27% lower in pilocarpine-treated rats during the chronic phase (Yakushev et al., 2009), which could correlate with the changes we observed in that region. It is also noteworthy that despite the lack of generalized seizures, the regions visualized corresponded to typical locations of neuronal damage, such as the septum, thalamus, amygaloid complex, piriform and entorhinal cortices (Turski et al., 1983b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activated microglia have been associated with neurodegeneration in patients and in animal models of Temporal Lobe Epilepsy (TLE), however their precise functions as neurotoxic or neuroprotective is a topic of significant investigation. To explore this, we examined the effects of pilocarpine-induced seizures in transgenic mice where microglia/macrophages were conditionally ablated. We found that unilateral ablation of microglia from the dorsal hippocampus did not alter acute seizure sensitivity. However, when this procedure was coupled with lipopolysaccharide (LPS) preconditioning (1 mg/kg given 24 h prior to acute seizure), we observed a significant pro-convulsant phenomenon. This effect was associated with lower metabolic activation in the ipsilateral hippocampus during acute seizures, and could be attributed to activity in the mossy fiber pathway. These findings reveal that preconditioning with LPS 24 h prior to seizure induction may have a protective effect which is abolished by unilateral hippocampal microglia/macrophage ablation.
    Neurobiology of Disease 04/2010; 39(1):85-97. DOI:10.1016/j.nbd.2010.04.001 · 5.20 Impact Factor
Show more