Allopurinol as Adjunctive Therapy in Intractable Epilepsy: A Double-blind and Placebo-controlled Trial

Togha, Mansoureh; Akhondzadeh, Shahin; Motamedi, Mahmood Reza Kalantar; Ahmadi, Babak; Razeghi, Soodeh

doi:10.1016/j.arcmed.2006.10.010

Cited by 43 publications

(31 citation statements)

References 10 publications

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“…Although not further addressed in these studies, energetic and mitochondrial dysfunction may be directly linked to adenosine, which has been described as a retaliatory metabolite adjusting energy consumption to energy supplies (Newby et al, 1985). A recent study used the purinergic drug allopurinol as adjunctive therapy in a double-blind and placebo-controlled trial in intractable epilepsy (Togha et al, 2007). This study demonstrated increased seizure reduction in the allopurinol group compared to control; however data were statistically significant only after 4 months of treatment, and allopurinolinduced side effects were common.…”

Section: Adenosine In Human Epilepsymentioning

confidence: 95%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Section: Adenosine In Human Epilepsymentioning

confidence: 95%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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“…2C) as adjunctive therapy is effective in seizure reduction [172][173][174][175][176], in which allopurinol may act via a decrease of Ado and/or Guo degradation and an HGPRT-induced increase in Ado and Guo levels (Fig. 1) [30,173].…”

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

confidence: 99%

“…1) [30,173]. Because of its relatively mild and negligible side effects, it was concluded that allopurinol may be an effective and safe adjuvant against intractable epilepsy [173].…”

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…Recent findings from human studies suggest energetic dysfunction and mitochondrial dysfunction to be implicated in epileptogenesis (Kunz, 2002;Pan et al, 2005;Williamson et al, 2005). Therapeutically, the purinergic drug allopurinol was used as adjunctive therapy in a double-blind and placebo-controlled trial in intractable epilepsy (Togha et al, 2007). Remarkably, seizures were decreased in the allopurinol group compared to control, however allopurinol-induced side effects were common.…”

Section: Clinical Findingsmentioning

confidence: 99%

Adenosine dysfunction in astrogliosis: cause for seizure generation?

et al. 2007

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Epilepsy is characterized by both neuronal and astroglial dysfunction. The endogenous anticonvulsant adenosine, the level of which is largely controlled by astrocytes, might provide a critical link between astrocyte and neuron dysfunction in epilepsy. Here we studied astrogliosis, a hallmark of the epileptic brain, adenosine dysfunction and the emergence of spontaneous seizures in a comprehensive approach including a new mouse model of focal epileptogenesis, mutant mice with altered brain levels of adenosine, and mice lacking adenosine A 1 receptors. In wild type mice, following a focal epileptogenesis-precipitating injury, astrogliosis, upregulation of the adenosineremoving astrocytic enzyme adenosine kinase (ADK), and spontaneous seizures all coincided in a spatio-temporally restricted manner. Importantly, these spontaneous seizures were mimicked in untreated transgenic mice overexpressing ADK in brain or those lacking A 1 receptors. Conversely, mice with reduced forebrain ADK did not develop astrogliosis or spontaneous seizures. Our studies define ADK as critical upstream regulator of A 1 receptor mediated modulation of neuronal excitability and support the ADK hypothesis of epileptogenesis implicating that upregulation of ADK during astrogliosis provides a critical link between astrocyte and neuron dysfunction in epilepsy. These findings define ADK as rational target for therapeutic intervention.

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Allopurinol as Adjunctive Therapy in Intractable Epilepsy: A Double-blind and Placebo-controlled Trial

Cited by 43 publications

References 10 publications

The adenosine kinase hypothesis of epileptogenesis

The adenosine kinase hypothesis of epileptogenesis

The Antiepileptic Potential of Nucleosides

Adenosine dysfunction in astrogliosis: cause for seizure generation?

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