Folia Pharmacologica Japonica
Online ISSN : 1347-8397
Print ISSN : 0015-5691
ISSN-L : 0015-5691
Volume 152, Issue 6
Displaying 1-7 of 7 articles from this issue
Reviews: Cutting-edge Topics in Epilepsy Research — Seeking for Novel Antiepileptics
  • Schuichi Koizumi, Fumikazu Sano
    2018 Volume 152 Issue 6 Pages 268-274
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Epilepsy is one of the most common diseases of the central nervous system. Many epilepsies are controllable because of the existence of different antiepileptic drugs with multiple mechanisms of action. However, about 30% of epilepsy is so-called refractory epilepsy in which existing drugs do not show enough therapeutic effects. Antiepileptic drugs can be roughly divided into two types, i.e., those that suppress the excitability of neuronal cells and those that promote inhibition. Inhibition of excitatory neurons include a variety of ion channel inhibitors such as Na+, drugs that inhibit glutamate release and glutamate AMPA receptor, whereas enhancement of inhibitory neurons includes a drug that enhances GABAA receptor. Both are targeted to neurons. Recent advances in brain science have revealed the importance of the role of glial cells in regulation of brain function and excitability of neurons. Although glia cells themselves are electrically non-excitable cells, they could greatly affect excitability of neurons by controlling extracellular neurotransmitters, glial transmitters, regulating various ions concentration, regulation of energy metabolism, and formation/elimination of synapses. Therefore, when the function of glial cells changes, these regulatory functions also change, which in turn greatly changes the excitability of neurons and neuronal networks. Epilegenicity is a condition in which the brain is likely to undergo spontaneous epileptic seizures and it is suggested that modulation of the above-mentioned glial cell function is greatly related to the acquisition of epileptogenesis. In this article, I focus on astrocytes among glial cells, and describe the relationship between functional modulation and epileptogenesis when changing to the phenotype of reactive astrocytes by epileptic seizures. We also discuss development of antiepileptic drugs targeting reactive astrocytes.

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  • Kentaro Tokudome, Saki Shimizu, Tadao Serikawa, Yukihiro Ohno
    2018 Volume 152 Issue 6 Pages 275-280
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Epilepsy is a chronic neurologic disease characterized by recurrent seizures, affecting nearly 1% of the population. Synaptic vesicle protein 2A (SV2A) is a membrane protein specifically expressed in synaptic vesicles and is now implicated in the pathogenesis of epileptic disorders. This is because 1) Sv2a-knockout mice exhibit severe seizures, 2) SV2A serves as a specific binding site for certain antiepileptics (e.g., levetiracetam and its analogues) and 3) the SV2A expression changes under various epileptic conditions both in animals (e.g., kindling) and humans (e.g., intractable temporal lobe epilepsy and focal cortical dysplasia). Furthermore, it has been shown that a missense mutation in the SV2A gene caused intractable epilepsy, involuntary movements and developmental retardation, indicating a causative role of SV2A dysfunction in epilepsy. In order to explore the mechanism of SV2A in modulating development of epileptogenesis, we recently developed a novel rat model (Sv2aL174Q rat) carrying a missense mutation (Leu174Gln) in the Sv2a gene. These rats were highly susceptible to the kindling development associated with repeated pentylenetetrazole treatments or electrical stimulations of the amygdala. In addition, the Sv2aL174Q mutation specifically impaired depolarization-induced GABA, but not glutamate, release in the hippocampus and amygdala. All this evidence indicates that the SV2A-GABAergic system plays a crucial role in modulating epileptogenesis and encourages discovery research into the novel antiepileptic agents which enhance the function of the SV2A-GABA system.

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  • Saeko Ishida
    2018 Volume 152 Issue 6 Pages 281-285
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Epilepsy is one of the most frequent neurological disorders characterized by spontaneous and recurrent seizures. Most seizures last for the lifetime and the patients require long term therapies. However, about 30% of the patients are refractory to antiepileptic drugs. Therefore, the need for newer and more effective therapies is urgent. Focal epilepsies, in which the abnormal electrical discharges occur within neuronal networks limited to one hemisphere, accounts for about 60% of all adult idiopathic epilepsy cases. Recently, mutations of DEPDC5 gene has been reported in wide spectrum of focal epilepsy syndromes. Most epilepsy genes encode ion channel or transmitter receptor, but DEPDC5 has no homology with them. DEPDC5 forms a complex, named GATOR1, together with other focal epilepsy related proteins NPRL2 and NPRL3. GATOR1 inhibits the mTORC1 pathway, regulating multiple cellular processes including cell growth and proliferation. The role of DEPDC5 in neuronal system is becoming clear from recent studies using the animal models. Because DEPDC5 is the most common causative gene in focal epilepsies and different from other epilepsy genes, DEPDC5 will be a key to understand epileptogenesis of various epilepsies, and provide new insight to develop new versatile therapies.

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Reviews: CNS Diseases are the Breakdown of the Homeostasis Maintaining Mechanisms — The New Interpretation Leads to New Therapeutic Strategies
  • Kaoru Sato
    2018 Volume 152 Issue 6 Pages 287-294
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Blood vessels in the central nervous system (CNS) limit the material exchange between blood and parenchyma by blood brain barrier (BBB). At present, no appropriate in vitro BBB models are available for the investigation whether or not the candidate compounds for new drugs could be delivered to the CNS. This causes huge difficulties of the development of CNS drugs and prediction of CNS adverse effects. In this review, I first outline the structures and functions of BBB, together with the parameters used for the quantification of BBB functions. I also introduce the history of in vitro BBB models used in the drug development so far, i.e., the transition from non-cell models to the models using primary culture of rodent cells, porcine, bovine, cell lines, etc. More recently, the application of human cells differentiated from human induced pluripotent stem cells and microfluidic engineering have already started. BBB is essential for the maintenance of brain homeostasis and the mechanisms of the BBB development will be clarified by reproducing functional BBB on the dish. The new in vitro models and the data may provide accurate prediction of drug delivery to the CNS and the improvement of the evaluation system for toxicity and safety, thereby leading to successful launch of new drugs on the market.

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  • Takatoshi Hikida
    2018 Volume 152 Issue 6 Pages 295-298
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Behavioral inflexibility has been reported in various psychiatric disorders including drug addiction and schizophrenia. Considerable evidence has demonstrated a critical role for the basal ganglia in the flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs) in the basal ganglia circuit. We used a reversible neurotransmission blocking technique to examine the role of D1- and D2-MSNs in the acquisition and reversal learning of a place discrimination task in the IntelliCage. We demonstrated that D1- and D2-MSNs do not mediate the acquisition of the task, but that suppression of activity in D2-MSNs impairs reversal learning and increased perseverative errors. Additionally, global knockout of the dopamine D2L receptor isoform produced a similar behavioral phenotype to D2-MSN-blocked mice. We also showed that D2L receptors are necessary for visual discrimination and reversal learning. These results suggest that D2L receptors and D2-MSNs have a critical role in the homeostatic regulation of basal ganglia circuit for flexible behaviors.

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  • Shigeki Moriguchi, Satomi Kita, Takahiro Iwamoto, Kohji Fukunaga
    2018 Volume 152 Issue 6 Pages 299-305
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Na+/Ca2+ exchanger (NCX) is mainly expressed in the plasma membrane and mediates electrogenical exchange of one Ca2+ for three Na+, depending on the electrochemical gradients across the plasma membrane. NCX has three different isoforms (NCX1, NCX2, NCX3) encoded by distinct genes in mammals. Here, we report that NCX2 and NCX3 protein levels are relatively reduced in hippocampal CA1 of Alzheimer’s disease model mice. Likewise, NCX2+/− or NCX3+/− mice exhibited impaired hippocampal LTP and memory-related behaviors. In immunoblot analyses, calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation significantly decreased in hippocampal CA1 of NCX2+/− mice compared to wild-type mice. By contrast, NCX2+/− mice was correlated with elevated calcineurin (CaN) activity and rescued by treatment with the calcineurin inhibitor FK506. Taken together, the imbalance of CaMKII and CaN activities with concomitant LTP impairment likely accounts for the learning disability observed in NCX2+/− mice.

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Review on New Drug
  • Takuma Harada, Ayako Ijima
    2018 Volume 152 Issue 6 Pages 306-318
    Published: 2018
    Released on J-STAGE: December 08, 2018
    JOURNAL FREE ACCESS

    Palbociclib is the world’s first cyclin dependent kinase (CDK) 4 and 6 inhibitor. It’s believed that palbociclib stops the cell cycle progression by inhibiting the activity of the complex consisting of CDK 4/6 and cyclin D, and suppresses tumor growth. In preclinical study using nonclinical model, it was confirmed that most of the cell lines sensitive to palbociclib are estrogen receptor (ER) positive. In addition, it was suggested that the expression of retinoblastoma protein (Rb) is needed for palbociclib to show its antitumor effect. By the preclinical studies using ER positive human breast cancer cell lines in combination administration of palbociclib and anti-estrogen drugs, it was confirmed that the antitumor effect was enhanced as compared with single agent administration of each drug. Based on these findings, the clinical studies in which hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced or metastatic breast cancer were conducted in combination with endocrine therapy. The PALOMA-2 study showed that progression-free survival (PFS) was longer with palbociclib plus letrozole than with placebo plus letrozole in the initial treatment of postmenopausal women with ER+/HER2− advanced breast cancer. In the PALOMA-3 study, the combination of palbociclib and fulvestrant was associated with significant improvements in PFS compared with fulvestrant plus placebo in patients with metastatic breast cancer. The rate of dose reduction or interruption of dosing by adverse events is higher in palbociclib group compared with placebo group in both studies while the rate of discontinuation of treatment was comparable.

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