Astrocytes derived from fetal neural progenitor cells as a novel source for therapeutic adenosine delivery

Laboratory for Clinical and Experimental Neurophysiology, Department of Neurology, Ghent University Hospital, 1K12, 185 De Pintelaan, 9000 Ghent, Belgium.
Seizure (Impact Factor: 1.82). 09/2010; 19(7):390-6. DOI: 10.1016/j.seizure.2010.05.010
Source: PubMed


Intracerebral delivery of anti-epileptic compounds represents a novel strategy for the treatment of refractory epilepsy. Adenosine is a possible candidate for local delivery based on its proven anti-epileptic effects. Neural stem cells constitute an ideal cell source for intracerebral transplantation and long-term drug delivery. In order to develop a cell-based system for the long-term delivery of adenosine, we isolated neural progenitor cells from adenosine kinase deficient mice (Adk(-/-)) and compared their differentiation potential and adenosine release properties with corresponding wild-type cells.
Fetal neural progenitor cells were isolated from the brains of Adk(-/-) and C57BL/6 mice fetuses and expanded in vitro. Before and after neural differentiation, supernatants were collected and assayed for adenosine release using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Adk(-/-) cells secreted significantly more adenosine compared to wild-type cells at any time point of differentiation. Undifferentiated Adk(-/-) cells secreted 137+/-5 ng adenosine per 10(5) cells during 24 h in culture, compared to 11+/-1 ng released from corresponding wild-type cells. Adenosine release was maintained after differentiation as differentiated Adk(-/-) cells continued to release significantly more adenosine per 24 h (47+/-1 ng per 10(5) cells) compared to wild-type cells (3+/-0.2 ng per 10(5) cells).
Fetal neural progenitor cells isolated from Adk(-/-) mice--but not those from C57BL/6 mice--release amounts of adenosine considered to be of therapeutic relevance.

Download full-text


Available from: Alain Verstraete
  • Source
    • "In addition, the primary role of ADK in the settlement of extracellular Ado level is supported by the fact that ADK overexpression reduces Ado tone [114]. In contrast, Ado secretion is significantly enhanced in ADK knockout mice compared to wild-type animal [115] and increased Ado level due to ADK inhibition attenuates neuronal firing rate [116]. From the pharmacological point of view it is also important that ADK expression level is known to be elevated both in animal models and in human temporal lobe epilepsy samples [117] and reduction of ambient Ado level by ADK overexpression triggers seizures [118, 119]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Ado-releasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.
    Full-text · Article · Feb 2015 · Current Medicinal Chemistry
  • Source
    • "Implantation of adenosine-releasing human mesenchymal cell grafts has an anticonvulsant and neuroprotective effect in an acute seizure model, and gives a seizure reduction when implanted 24 h after intraamygdaloid KA injection (Ren et al., 2007; Li et al., 2009). Recently, also adenosine kinase knockout fetal stem cells were isolated as a potential cell source for local delivery of adenosine in animals with refractory epilepsy (Van Dycke et al., 2010a,b). However, the efficacy of stem cell transplantation must also be demonstrated in clinically relevant animal models with chronic spontaneous seizures. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite different treatment options for patients with refractory epilepsy such as epilepsy surgery and neurostimulation, many patients still have seizures and/or drug-related cerebral and systemic side effects. Local intracerebral delivery of antiepileptic compounds may represent a novel strategy with specific advantages such as the option of higher local doses and reduced side effects. In this study we evaluate the antiepileptic effect of local delivery of adenosine in the kainic acid rat model, a validated model for temporal lobe epilepsy. Fifteen rats, in which intraperitoneal kainic acid injection had induced spontaneous seizures, were implanted with a combination of depth electrodes and a cannula in both hippocampi. Cannulas were connected to osmotic minipumps to allow continuous hippocampal delivery. Rats were freely moving and permanently monitored by video-EEG (electroencephalography). Seizures were scored during 2 weeks of local hippocampal delivery of saline (baseline), followed by 2 weeks of local adenosine (6 mg/ml) (n = 10) or saline (n = 5) delivery (0.23 μl/h) (treatment). In 7 of 10 adenosine-treated rats, saline was also delivered during a washout period. During the treatment period a mean daily seizure frequency reduction of 33% compared to the baseline rate was found in adenosine-treated rats (p < 0.01). Four rats had a seizure frequency reduction of at least 50%. Both nonconvulsive and convulsive seizures significantly decreased during the treatment period. In the saline-control group, mean daily seizure frequency increased with 35% during the treatment period. This study demonstrates the antiseizure effect of continuous adenosine delivery in the hippocampi in rats with spontaneous seizures.
    Full-text · Article · Sep 2010 · Epilepsia
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Astrocytes are the predominant glial cell population in the central nervous system (CNS). Once considered only passive scaffolding elements, astrocytes are now recognised as cells playing essential roles in CNS development and function. They control extracellular water and ion homeostasis, provide substrates for energy metabolism, and regulate neurogenesis, myelination and synaptic transmission. Due to these multiple activities astrocytes have been implicated in almost all brain pathologies, contributing to various aspects of disease initiation, progression and resolution. Evidence is emerging that astrocyte dysfunction can be the direct cause of neurodegeneration, as shown in Alexander’s disease where myelin degeneration is caused by mutations in the gene encoding the astrocyte-specific cytoskeleton protein glial fibrillary acidic protein. Recent studies point to a primary role for astrocytes in the pathogenesis of other genetic leukodystrophies such as megalencephalic leukoencephalopathy with subcortical cysts and vanishing white matter disease. The aim of this review is to summarize current knowledge of the pathophysiological role of astrocytes focusing on their contribution to the development of the above mentioned leukodystrophies and on new perspectives for the treatment of neurological disorders.
    Full-text · Article · Jun 2013
Show more