Necl2/3-mediated mechanism for tripartite synapse formation.

Ramified, polarized protoplasmic astrocytes interact with synapses via perisynaptic astrocyte processes (PAPs) to form tripartite synapses. These astrocyte-synapse interactions mutually regulate their structures and functions. However, molecular mechanisms for tripartite synapse formation remain elusive. We developed an in vitro co-culture system for mouse astrocytes and neurons that induced astrocyte ramifications and PAP formation. Co-cultured neurons were required for astrocyte ramifications in a neuronal activity-dependent manner, and synaptically-released glutamate and activation of astrocytic mGluR5 metabotropic glutamate receptor were likely involved in astrocyte ramifications. Astrocytic Necl2 trans-interacted with axonal Necl3, inducing astrocyte-synapse interactions and astrocyte functional polarization by recruiting EAAT1/2 glutamate transporters and Kir4.1 K+ channel to the PAPs, without affecting astrocyte ramifications. This Necl2/3 trans-interaction increased functional synapse number. Thus, astrocytic Necl2, synaptically-released glutamate and axonal Necl3 cooperatively formed tripartite glutamatergic synapses in vitro. Studies on hippocampal mossy fiber synapses in Necl3 knockout and Necl2/3 double knockout mice confirmed these previously unreported mechanisms for astrocyte-synapse interactions and astrocyte functional polarization in vivo.

[Preclinical and clinical efficacy of orexin receptor antagonist Lemborexant (Dayvigo®) on insomnia patients].

Orexin receptor antagonists have been approved for insomnia, and the insomnia pharmacotherapy is being greatly progressed. Orexin is a neuropeptide produced in the lateral hypothalamic area, and its physiological role has been suggested to be a key mediator controlling the sleep-wake state. Orexin receptor antagonists are thought to induce physiological sleep by acting specifically on the sleep-wake cycle. Lemborexant is a dual antagonist acting on both two orexin receptors, the orexin 1 (OX1R) and 2 receptor (OX2R), with stronger inhibitory effects on OX2R. Since it binds to and dissociates from orexin receptors rapidly, the pharmacokinetics of its blood concentration may have an impact on its pharmacological action. In rats, lemborexant exhibited a sleep-inducing effect without altering sleep architecture. In the phase III studies in patients with insomnia, lemborexant significantly improved difficulties in falling asleep and maintaining sleep. While somnolence occurred as treatment-related adverse events in a dose-dependent manner, lemborexant was generally well-tolerated. Also, the effects on body sway and driving skills 8-9 hours after administration did not differ from those in the placebo group, suggesting little next morning residual effects. Subgroup analysis has shown that efficacy and safety of lemborexant were similar in patients with insomnia with comorbidities, suggesting lemborexant may also be useful for those patients. Based on the above results and others, lemborexant has been approved for the indication of insomnia in January 2020 in Japan. Lemborexant will give a new treatment option for patients with insomnia.

[Safinamide Mesilate (Equfina® TABLETS 50†mg): preclinical and clinical pharmacodynamics, efficacy, and safety].

Parkinson's disease is a neurodegenerative disorder characterized by the degenerative loss of dopaminergic neurons in the substantia nigra. Dopamine deficiency is thought to disrupt motor control of the basal ganglia and cause characteristic motor symptoms in Parkinson's disease such as bradykinesia, akinesia, and tremor. Therefore, dopamine replacement therapy is widely used in the clinical setting. Safinamide is a novel, selective, and reversible inhibitor of monoamine oxidase B expected to increase dopamine levels in the brain and improve the symptoms of Parkinson's disease. In addition, safinamide shows non-dopaminergic actions such as sodium channel blockade and inhibition of glutamate release. Preclinical studies have demonstrated that safinamide ameliorates "wearing off" symptoms after administration in rat and monkey models with selectively destroyed dopaminergic neurons. In the monkeys, safinamide concurrently inhibited levodopa-induced dyskinesia. These findings suggest that safinamide not only increases the dopaminergic effect of levodopa, but also reduces levodopa-induced adverse events via its non-dopaminergic effects. In clinical trials of patients with Parkinson's disease with the "wearing off" phenomenon, safinamide has been found to prolong the "on time" and improve motor function as assessed by Unified Parkinson's Disease Rating Scale Part III. In Japan, safinamide was approved in September 2019 as a levodopa combination drug for Parkinson's disease with "wearing off" phenomenon. Safinamide is therefore expected to be a new treatment option for patients with Parkinson's disease.