Takanari Toyoda

Apraxia of eyelid opening after subthalamic deep brain stimulation may be caused by reduction of levodopa.

Apraxia of eyelid opening (ALO) is an infrequent side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinsons disease (PD). However, the pathogenesis of ALO after STN DBS is not well understood. We report on two patients who suffered from disabling ALO after bilateral STN DBS. Their ALO improved by resuming the levodopa medication that had been discontinued after the surgery. Although ALO after STN DBS is considered as an adverse effect of STN stimulation, postoperative modification of dopaminergic medication may be a cause of ALO after STN DBS.

Predictive factors affecting early deterioration of axial symptoms after subthalamic nucleus stimulation in Parkinson's disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment option for medically refractory Parkinsons disease (PD). However, some patients show deterioration of axial symptoms within a short time after surgery. We studied 43 patients who underwent bilateral STN-DBS and investigated predictive factors affecting early deterioration of axial symptoms. Among 43 patients, 16 patients showed obvious deterioration of axial symptoms within three years of surgery. Multiple logistic regression analysis indicated that the significant independent variables related to early deterioration of axial symptoms were rapidly progressive short duration of the disease and advanced age at surgery. These results suggest that patients with rapidly progressing PD, who need early surgical intervention, tend to show early deterioration of axial symptoms after STN-DBS.

Directed neural lineage differentiation of adult hippocampal progenitor cells via modulation of hippocampal cholinergic neurostimulating peptide precursor expression

Hippocampal cholinergic neurostimulating peptide (HCNP), originally purified from young rat hippocampus, has been known to promote the differentiation of septo-hippocampal cholinergic neurons. Recently, the precursor protein of HCNP (HCNP-pp) has also received attention as a multifunctional protein with roles, in addition to serving as the HCNP precursor, such as acting as an ATP-binding protein, a Raf kinase inhibitor protein (RKIP), and phosphatidylethanolamine-binding protein (PEBP). In particular, the function of RKIP has attracted attention over several years for its role in controlling cellular proliferation and metastasis in cancer cells. HCNP-pp is also thought to be important in regulating the proliferation and differentiation of neuronal cells in vitro and in vivo by modification of the MAPK cascade. In the present study, we used cultured adult rat hippocampal progenitor cells (AHPs), which are thought to be important for memory formation, and focused on the role of HCNP-pp in adult neurogenesis, namely, the production of new neurons from neural stem/progenitor cells. We found that HCNP-pp expression in AHPs was closely associated with differentiation into MAP2ab-positive neurons and RIP-positive oligodendrocytes, but not into GFAP-positive astrocytes. By contrast, a down-regulated HCNP-pp expression in AHPs accompanied differentiation into GFAP-positive astrocytes. Direct manipulations of HCNP-pp via viral over-expression or siRNA downregulation further confirmed the HCNP-pp contribution to specific neural lineage commitment of AHPs. Our results show that the expression level of HCNP-pp acts as a key regulator for differentiation of cultured AHPs into specific neural lineages, indicating that the control of neural stem cell fate can be achieved via the HCNP-pp pathway.

Overexpression of hippocampal cholinergic neurostimulating peptide in heterozygous transgenic mice increases the amount of ChAT in the medial septal nucleus.

Acetylcholine modulates neural activity in the hippocampal glutamatergic pathway via the induction of phosphorylated Erk and may act as a novel transmitter in septohippocampal memory formation. However, how acetylcholine synthesis in the septal nucleus is regulated is unknown. We have purified a peptide from the hippocampus of the young adult rat, named hippocampal cholinergic neurostimulating peptide (HCNP) that induces acetylcholine synthesis in vitro in the septal nucleus. Previously, levels of this peptide and/or precursor protein were reported to be decreased, and the protein to be nitrated in the brains of patients with Alzheimers disease. Here, to clarify the involvement in the regulation of acetylcholine synthesis in vivo in the medial septal nucleus, we generated HCNP precursor transgenic mice, using a Ca2+ calmodulin-dependent protein kinase II genomic promoter. The amount of cholineacetyltransferase (ChAT) in the medial septal nucleus was increased in heterozygous HCNP transgenic mice, compared with non-transgenic littermates. This result suggests that HCNP is involved in regulating acetylcholine synthesis in vivo in the medial septal nucleus and, as such, is important for memory function.

Suppressed phosphorylation of collapsin response mediator protein-2 in the hippocampus of HCNP precursor transgenic mice

We previously reported a novel peptide, Hippocampal Cholinergic Neurostimulating Peptide (HCNP), which induces acetylcholine synthesis by increasing the amount of choline acetyltransferase (ChAT) in medial septal nuclei. The HCNP precursor protein (HCNP-pp), composed of 186 amino acids, is an inhibitory factor of the c-Raf/MEK cascade and may be involved in fetal rat brain development via the inhibition of phosphorylation of Erk. To clarify the involvement of HCNP in hippocampal cholinergic circuitry, we previously generated HCNP-pp transgenic (HCNP-pp Tg) mice using the promoter of the α subunit of Ca(2+) calmodulin-dependent protein kinase II (CaMKIIα). These mice showed increased levels of ChAT in medial septal nuclei at 12 weeks of age, and the phenotype of depressive mood at 30 weeks of age. Here, through proteomic analysis we investigated the alteration of protein expression in the hippocampus of HCNP-pp Tg mice compared with wild-type littermate mice. We demonstrate that the activation of collapsin response mediator protein-2 (CRMP-2) is increased in the transgenic mice at 12 weeks of age when compared with wild-type littermate mice.

Suppression of Astrocyte Lineage in Adult Hippocampal Progenitor Cells Expressing Hippocampal Cholinergic Neurostimulating Peptide Precursor in an In Vivo Ischemic Model

Hippocampal cholinergic neurostimulating peptide (HCNP) is known to promote differentiation of septohippocampal cholinergic neurons. The HCNP precursor protein (HCNP-pp) may play several roles, for example, as an ATP-binding protein, a Raf kinase inhibitor protein, and a phosphatidylethanolamine-binding protein, as well as a precursor for HCNP. This study therefore aimed to elucidate the involvement of HCNP-pp in specific neural lineages after stroke using a hypoxic–ischemic (HI) rat model of brain ischemia. The specific neural lineages in the hippocampus were investigated 14 days after ischemia. Some bromodeoxyuridine (BrdU)+ neural progenitor cells in the hippocampus of hypoxic, HI, or sham-operated rats expressed HCNP-pp. Almost half of the BrdU+/HCNP-pp+ cells also expressed the oligodendrocyte lineage marker 2′,3′-cyclic nucleotide 3′-phosphodiesterase, whereas only a few BrdU+/HCNP-pp+ cells in the hippocampus in HI brains expressed the neuronal lineage marker, doublecortin (DCX). Interestingly, no BrdU+/HCNP-pp+ progenitor cells in hypoxic, HI, or sham-operated brains expressed the astrocyte lineage marker, glial fibrillary acidic protein. Together with previous in vitro data, the results of this study suggest that the expression level of HCNP-pp regulates the differentiation of neural progenitor cells into specific neural lineages in the HI hippocampus, indicating that neural stem cell fate can be controlled via the HCNP-pp mediating pathway.

Combination of ketogenic diet and stiripentol for super-refractory status epilepticus: A case report

Super-refractory status epilepticus (SRSE) is defined as status epilepticus (SE) that continues for at least 24 h after initiation of general anaesthetic medications, including cases in which SE recurs on reduction or withdrawal of anaesthesia [1]. Given the severity of SRSE, there is a critical need for new therapies to halt ongoing seizure activity. Because neuronal excitation is regulated by energy metabolism, SRSE can be suppressed by inhibiting metabolic pathways. A ketogenic diet (KD) has been proven to be effective in critically ill adults with SRSE [2]; however, the mechanisms by which KD prevents seizures remain unknown. It has recently been found that one of the mechanisms that KD works on is a metabolic pathway via lactate dehydrogenase (LDH) and that LDH may be inhibited by stiripentol (STP) [3]. Here, we report that a combination of KD and STP appeared to constitute effective treatment of a patient with SRSE underlying anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. A 20-year-old Japanese woman presented with a week of headaches followed by impaired consciousness. On admission, she exhibited abnormal behaviours, including altered manner of speaking and shouting loudly. She was unable to follow commands and became unresponsive to external stimuli. An electroencephalogram (EEG) showed generalized rhythmic delta frequency activity at 1 Hz with superimposed, frontally predominant bursts of rhythmic beta frequency activity (extreme delta brushes) (Fig. 1(A-1)). Her cerebrospinal fluid demonstrated mild pleocytosis (74 cells per mm) with a slightly elevated IgG index (1.01). Glucose and protein concentrations were normal. She was diagnosed as having NMDAR encephalitis (positive anti-NMDAR antibody result) with bilateral ovarian teratomas (pelvic CT findings) (Fig. 1(B)). Her symptoms were not alleviated by bilateral ovariectomy and immunotherapy (plasma exchange, intravenous immunoglobulin at 400 mg/kg over 5 days and intravenous methylprednisolone at 1000 mg over 3 days). Additionally, her seizures were unresponsive to conventional antiepileptic drugs (AEDs) such as valproate, carbamazepine, phenytoin, clonazepam, phenobarbital, and levetiracetam. Further, these treatments repeatedly resulted in a generalized rash accompanied by fever, leukopenia, and acute hepatitis and they were accordingly ceased.

Two brothers homozygous for the TTR V30M both presenting with a phenotype dominated by central nervous complications

Department of Neurology, Toyokawa City Hospital, 23 Noji, Yawata-cho, Toyokawa 442-8561, Aichi, Japan, Department of Neurology, Kumamoto University, Kumamoto, Japan, Department of Radiology, Toyokawa City Hospital, Aichi, Japan, Department of Neurology, Nagoya University, Aichi, Japan, Department of Neurosurgery, Toyokawa City Hospital, Aichi, Japan, and Department of Neurology, Nagoya City University, Aichi, Japan

Phosphorylation of collapsin response mediator protein-2 regulates its localization and association with hippocampal cholinergic neurostimulating peptide precursor in the hippocampus

Hippocampal cholinergic neurostimulating peptide (HCNP) induces the synthesis of acetylcholine in the medial septal nucleus in vitro and in vivo. The precursor, HCNP-pp, is a multifunctional protein participating in important signaling pathways, such as MAPK/ERK kinase (MEK) and G-protein-coupled receptor kinase 2 (GRK2). We recently demonstrated that HCNP-pp colocalizes with collapsin response mediator protein-2 (CRMP-2) at presynaptic terminals in the hippocampus, suggesting that HCNP-pp may play an important role in presynaptic function in association with CRMP-2. To clarify the involvement of phosphorylation in regulating the interaction between HCNP-pp and CRMP-2, we investigated the colocalization of HCNP-pp with unphosphorylated- and/or phosphorylated-CRMP-2 (pCRMP-2) at presynaptic terminals. We further determined if the phosphorylation of CRMP-2 affects the binding between those proteins. Here, we demonstrate that HCNP-pp predominantly colocalizes and associates with unphosphorylated and/or pSer-522-CRMP-2 at presynaptic terminals in the hippocampus. Interestingly, HCNP-pp does not associate with pThr-509/514-CRMP-2, which is primarily localized at postsynaptic terminals. These findings suggest that HCNP-pp, in association with unphosphorylated and/or pSer522-CRMP-2, plays an important role in presynaptic function in the mature hippocampus.

Stiripentol for the treatment of super‐refractory status epilepticus with cross‐sensitivity

Cross‐sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross‐sensitivity in patients with super‐refractory status epilepticus (SRSE).