Human mesenchymal stem cell grafts engineered to release adenosine reduce chronic seizures in a mouse model of CA3-selective epileptogenesis

Robert Stone Dow Neurobiology Laboratories, Legacy Research, 1225 NE 2nd Avenue, Portland, OR 97232, USA.
Epilepsy research (Impact Factor: 2.02). 03/2009; 84(2-3):238-41. DOI: 10.1016/j.eplepsyres.2009.01.002
Source: PubMed


A novel generation of silk-based brain implants engineered to release adenosine was recently shown to provide robust seizure suppression in kindled rats. As a first step to develop stem cell-coated silk-based 3D-scaffolds for the therapeutic long-term delivery of adenosine we engineered human mesenchymal stem cells (hMSCs) to release adenosine. Here we demonstrate reduction of chronic seizures in a mouse model of CA3-selective epileptogenesis after infrahippocampal transplantation of adenosine-releasing hMSCs.

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Available from: Tianfu Li
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    • "For example , marrow cell transplantation have achieved promising results in models of acute injury such as ischemic brain damage [14] [15] [16], traumatic brain injury [17] [18] and spinal cord lesion [19] [20]. Findings by other teams point out that the therapeutic potential of bone marrow cells can also be of use in chronic and neurodegenerative ailments including multiple sclerosis [21] [22] [23], amyotrophic lateral sclerosis [24] [25], epilepsy [26] [27], Parkinson's disease [28] [29] and Alzheimer's disease [30] [31]. "

    Full-text · Dataset · Jun 2013
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    • "For instance, the maximum postseizure hyperpolarization under control conditions was Ϫ22.9 Ϯ 1.6 mV relative to baseline, and this was reduced to Ϫ15.5 Ϯ 1.9 mV when ARs were blocked (n ϭ 10, p Ͻ 0.01, paired t test; Fig. 1C). The adenosine-induced effects persisted for several minutes into the postseizure period, a time course that matches with previous reports of AR antagonism on the recovery of evoked field potentials (Etherington and Frenguelli, 2004; Etherington et al., 2009). More generally, our data demonstrate that ARs are strongly activated during seizures and function to attenuate seizure activity. "
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    ABSTRACT: Seizure-induced release of the neuromodulator adenosine is a potent endogenous anticonvulsant mechanism, which limits the extension of seizures and mediates seizure arrest. For this reason several adenosine-based therapies for epilepsy are currently under development. However, it is not known how adenosine modulates GABAergic transmission in the context of seizure activity. This may be particularly relevant as strong activation of GABAergic inputs during epileptiform activity can switch GABA(A) receptor (GABA(A)R) signaling from inhibitory to excitatory, which is a process that plays a significant role in intractable epilepsies. We used gramicidin-perforated patch-clamp recordings to investigate the role of seizure-induced adenosine release in the modulation of postsynaptic GABA(A)R signaling in pyramidal neurons of rat hippocampus. Consistent with previous reports, GABA(A)R responses during seizure activity transiently switched from hyperpolarizing to depolarizing and excitatory. We found that adenosine released during the seizure significantly attenuated the depolarizing GABA(A)R responses and also reduced the extent of the after-discharge phase of the seizure. These effects were mimicked by exogenous adenosine administration and could not be explained by a change in chloride homeostasis mechanisms that set the reversal potential for GABA(A)Rs, or by a change in the conductance of GABA(A)Rs. Rather, A(1)R-dependent activation of potassium channels increased the cell's membrane conductance and thus had a shunting effect on GABA(A)R currents. As depolarizing GABA(A)R signaling has been implicated in seizure initiation and progression, the adenosine-induced attenuation of depolarizing GABA(A)R signaling may represent an important mechanism by which adenosine can limit seizure activity.
    Full-text · Article · Apr 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Local delivery through adenosine-secreting stem cells in the hippocampus already showed a delay in the progression of kindling development (Li et al., 2007; Wilz et al., 2008). 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). "
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    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
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