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Patients with neurological diseases, such as schizophrenia, tend to show low K+-Cl- co-transporter 2 (KCC2) levels in the brain. The cause of these diseases has been associated with stress and neuroinflammation. However, since the pathogenesis of these diseases is not yet fully investigated, drug therapy is still limited to symptomatic therapy. Targeting KCC2, which is mainly expressed in the brain, seems to be an appropriate approach in the treatment of these diseases. In this review, we aimed to discuss about stress and inflammation, KCC2 and Gamma-aminobutyric acid (GABA) function, diseases which decrease the KCC2 levels in the brain, factors that regulate KCC2 activity, and the possibility to overcome neuronal dysfunction targeting KCC2. We also aimed to discuss the relationships between neurological diseases and LPS caused by Porphyromonas gingivalis (P. g), which is a type of oral bacterium. Clinical trials on oxytocin, sirtuin 1 (SIRT1) activator, and transient receptor potential cation channel subfamily V Member 1 activator have been conducted to develop effective treatment methods. We believe that KCC2 modulators that regulate mitochondria, such as oxytocin, glycogen synthase kinase 3β (GSK3β), and SIRT1, can be potential targets for neurological diseases.

Kamishoyosan (KSS) and Kamikihito (KKT) have been traditionally prescribed for neuropsychiatric symptoms in Japan. However, the molecular mechanism of its effect is not elucidated enough. On the other hand, it has been reported that lipopolysaccharide derived from Porphyromonas gingivalis (P. g LPS) is involved not only in periodontal disease but also in the systemic diseases such as psychiatric disorders via neuroinflammation. Here, we investigated the molecular mechanism of KSS and KKT treatment by LPS-induced neuropathy using PC-12 cells. When P. g LPS was administrated during the NGF treatment, the KCC2 expression was decreased in PC-12 cells. P. g LPS treatment also decreased the WNK and phospho SPAK (pSPAK) expression and enhanced GSK-3β expression that negatively regulates WNK-SPAK signaling. Moreover, when KSS or KKT was administrated before P. g LPS treatment, the decrease of KCC2, WNK and pSPAK was rescued. KSS and KKT treatment also rescued the enhancement of GSK3β expression by P. g LPS treatment. Furthermore, KSS, KKT and/or oxytocin could rescue behavioral abnormalities caused by P. g LPS treatment by animal experiments. These effects were not shown in the Goreisan treatment, which has been reported to act on the central nervous system. These results indicate that KSS and KKT are candidates for therapeutic agents for neural dysfunction.

We characterized [methyl-3H]thymidine ([3H]thymidine) and [5-3H]uridine ([3H]uridine) incorporation into cultured astrocytes and neurons in the presence and absence of hydrogen peroxide (H2O2) in order to define the response to oxidative stress in the central nervous system. [3H]Thymidine incorporation into cultured astrocytes was remarkably decreased by N6,2’-O-dibutyryladenosine 3’,5’-cyclic monophosphate (DBcAMP), a permeable analogue of cAMP, which induced a morphological change from the polygonal form (undifferentiated astrocytes) to the process-bearing one (differentiated astrocytes). H2O2 induced [3H]thymidine, but not [3H]uridine, incorporation into cultured astrocytes at only an early time from 24 h after DBcAMP treatment, although the absolute quantities of [3H]thymidine incorporation into astrocytes pretreated with DBcAMP were less than those into astrocytes pretreated without DBcAMP. Hydroxyurea, a replicative DNA synthesis inhibitor, suppressed dose-dependently and completely [3H]thymidine incorporation into astrocytes pretreated without DBcAMP, but not astrocytes pretreated with DBcAMP. H2O2 did not stimulate [3H]thymidine or [3H]uridine incorporation into astrocytes pretreated without DBcAMP and neurons. These findings indicate that only astrocytes pretreated with DBcAMP are able to increase thymidine incorporation specifically in the presence of H2O2 for a purpose other than proliferation, including the repair of H2O2-induced DNA injury, for example. Keywords:: hydrogen peroxide (H2O2), thymidine incorporation, astrocyte, N6,2’-O-dibutyryladenosine 3’,5’-cyclic monophosphate (DBcAMP), hydroxyurea

To examine the effect of the arginine-vasopressin fragment, [pGlu4,Cyt6]AVP(4–9) (AVP4–9), on group II metabotropic glutamate receptor (mGluR2/3) agonist and antagonist induced impairment of passive avoidance (PA) task performance, AVP4–9 or phorbol 12-myristate 13-acetate (PMA) was administered in the presence of mGluR2/3-related drugs that induced the impairment of the step-through-type PA task performance. The PA task performance was evaluated in terms of the latency (the time that elapsed prior to entry into the dark compartment) at 24 h after the electrical stimulation. The subcutaneous injection of AVP4–9 at 1 μg/kg had the greatest facilitative effect on the performance, and the facilitative effect of AVP4–9 was inhibited by NPC-15437, a specific protein kinase C (PKC) inhibitor. The injection of AVP4–9 ameliorated PA task performance impairment induced by DCG-IV, an mGluR2/3 agonist. Intracisternal injection of PMA, a PKC activator, also ameliorated the DCG-IV-induced impairment. High doses of AVP4–9 exacerbated the PA task performance impairment induced by LY341495 (an mGluR2/3 antagonist), and PMA injection (1 μg) also exacerbated the impairment induced by the antagonist. These results suggest that an increase in the activity of the PKC-signaling pathway may not always facilitate PA task performance; therefore, AVP4–9 can either enhance or inhibit memory performance in mice. Keywords:: memory, [pGlu4,Cyt6]AVP(4–9), protein kinase C

We examined the effect of the acetylcholinesterase (ACHE) inhibitor, donepezil hydrocloride (DONP), on group II metabotropic glutamate (mGlu) receptor agonist- or antagonist-induced amnesia in the step-through passive avoidance task in male mice. DCG-IV, a group II mGlu receptor agonist, at dose of 50 ng and LY341495, a group II mGlu receptor antagonist, at dose of 300 ng, significantly attenuated the latency on the step-through task. The subcutaneous injection of DONP at dose of 1 mg/kg 1 hour before passive avoidance performance ameliorated the amnesia induced by DCG-IV and LY341495, whereas donepezil alone did not affect task latency. The results suggest that activation of group II mGlu receptors and disinhibition of the cAMP/PKA signaling pathway (caused by group II mGlu receptor antagonist) have a negative action on step-through passive avoidance memory performance, and that group II mGlu receptors and ACh interact to modulate learning and memory function.