The open neuroscience journal最新文献

Ketogenic diets are high in fat and low in carbohydrates and represent a well-established and effective treatment alternative to anti-epileptic drugs. Ketogenic diets are used for the management of a variety of difficult-to-treat or intractable seizure disorders, especially pediatric refractory epilepsy. However, it has been shown that this dietary therapy can reduce seizures in people of all ages, and ketogenic diets are being applied to other prevalent medical conditions such as diabetes. Although used effectively to treat epilepsy for nearly 90 years, the mechanism(s) by which ketogenic diets work to reduce seizures remain ill-understood. One mechanism receiving increased attention is based on findings that ketogenic diets increase the brain energy molecule ATP, and may also increase the levels and actions of the related endogenous inhibitory neuromodulator adenosine. ATP and adenosine have both been identified as important modulators of seizures; seizures increase the actions of these purines, these purines regulate epileptic activity in brain, adenosine receptor antagonists are pro-convulsant, and adenosinergic mechanisms have been implicated previously in the actions of approved anti-epileptic therapeutics. Here we will review recent literature and describe findings that shed light on mechanistic relationships between ketogenic diets and the purines ATP and adenosine. These emerging mechanisms hold great promise for the effective therapeutic management of epileptic seizures and other neurological conditions.

Traditionally, epilepsy has been considered to be a disorder of neuronal dysfunction. Based on this dogma, drug development efforts have largely focused on neurocentric model systems to screen for compounds that affect the function of neurons. Unfortunately, about 30% of all patients with epilepsy - or more than 20 million worldwide - are refractory to classical neurocentric pharmacotherapy. The failure of neurocentric pharmacotherapy in epilepsy requires radical rethinking and the search for novel therapeutic targets. Research from recent years suggests that epilepsy is a disorder of astrocyte dysfunction. Astrocytes are key regulators of the brain's own anticonvulsant adenosine. Thus, any dysfunction in astrocyte metabolism will drastically affect the brain's ability to control excitability via adenosinergic neuromodulation. This review will focus on the astrocyte-based enzyme adenosine kinase (ADK) as the key regulator of synaptic adenosine. Astrogliosis - a pathological hallmark of the epileptic brain - leads to overexpression of the adenosine-removing enzyme ADK and therefore to adenosine deficiency. Evidence from transgenic animals demonstrates that overexpression of ADK per se is sufficient to trigger seizures. Consequently, pharmacological inhibition of ADK is very effective in suppressing seizures that are refractory to classical antiepileptic drugs. The recent definition of ADK as rational target to predict and to prevent seizures in epilepsy has prompted the development of focal adenosine augmentation therapies (AATs) that have been designed to selectively reconstitute adenosinergic signalling within an area of astrogliosis-based adenosine-dysfunction. This therapeutic challenge has experimentally been met with polymeric or stem cell based brain implants to afford the focal delivery of adenosine.

Recent studies indicate that microtubules (MTs) may play an important role in spine development and dynamics. Several imaging studies have now documented the exploration of dendritic spines by dynamic MTs in an activity-dependent manner. Furthermore, it was found that alterations of MT dynamics by pharmacological and molecular approaches exert profound influence on the development and plasticity of spines associated with neuronal activity. It is reasonable to speculate that dynamic MTs may be responsible for targeted delivery of specific cargos to a selected number of spines and/or for interacting with the actin cytoskeleton to generate the structural changes of spines associated with synaptic modifications.