Intrastriatal Memantine Infusion

Although the administration of dopamine precursor levodopa remains as the mainstay for the treatment of Parkinson’s disease, long-term exposure to levodopa often causes a disabling complication, referred to as levodopa-induced dyskinesias. Therefore, the development of new therapeutic interventions to dampen levodopa-induced dyskinesias and parkinsonian motor deficits is needed in the treatment of Parkinson’s disease. Intracerebral brain infusion has the merit of being able to specifically deliver any drug into any brain part. By using an intracerebral infusion system equipped with implantable, programmable, and refillable pumps, we show herein that continuous intrastriatal administration of memantine (MMT), which is a non-competitive N-methyl-D-aspartate receptor antagonist, attenuates levodopa-induced dyskinesias and parkinsonian signs in 6-hydroxydopamine-lesioned hemiparkinsonian mice that received daily levodopa treatment. Corroborating the general thought that overactivation of the striatal N-methyl-D-aspartate receptor function might generate levodopa-induced dyskinesias and parkinsonism, our results suggest that a continuous intrastriatal MMT infusion can be beneficial for the management of Parkinson’s disease with levodopa-induced dyskinesias. Our study also provides indications for the prototypic use of pharmacological deep-brain modulation through intracerebral infusion systems for treating medically intractable movement disorders

Video-based assessments of the hind limb stepping in a mouse model of hemi-parkinsonism

Unilateral injection of 6-hydroxydopamine (6-OHDA) is commonly used to generate a rodent model of Parkinson’s disease (PD). Although motor deficits of the lower extremities represent one of the major clinical symptoms in PD patients, validated tests for assessing motor impairments of the hind limb in 6-OHDA mice are currently unavailable. We here report the video-based assessments of the asymmetric use of hind limbs in 6-OHDA mice. A significantly decreased number of spontaneous hind limb stepping was observed in the contralateral-to-lesioned side, and was dose dependently reversed by levodopa, suggesting that it could be utilized for screening PD therapeutics

c-Abl Inhibition Exerts Antiparkinsonian Effects

Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD

c-Abl Inhibition Exerts Symptomatic Antiparkinsonian Effects Through a Striatal Postsynaptic Mechanism

Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD

Infected aortic aneurysm and inflammatory aortic aneurysm—In search of an optimal differential diagnosis

SummaryInfected aortic aneurysm and inflammatory aortic aneurysm each account for a minor fraction of the total incidence of aortic aneurysm and are associated with periaortic inflammation. Despite the similarity, infected aortic aneurysm generally shows a more rapid change in clinical condition, leading to a fatal outcome; in addition, delayed diagnosis and misuse of corticosteroid or immunosuppressing drugs may lead to uncontrolled growth of microorganisms. Therefore, it is mandatory that detection of aortic aneurysm is followed by accurate differential diagnosis. In general, infected aortic aneurysm appears usually as a saccular form aneurysm with nodularity, irregular configuration; however, the differential diagnosis may not be easy sometimes for the following reasons: (1) symptoms, such as abdominal and/or back pain and fever, and blood test abnormalities, such as elevated C-reactive protein and enhanced erythrocyte sedimentation rate, are common in infected aortic aneurysm, but they are not found infrequently in inflammatory aortic aneurysm; (2) some inflammatory aortic aneurysms are immunoglobulin (Ig) G4-related, but not all of them; (3) the prevalence of IgG4 positivity in infected aortic aneurysm has not been well investigated; (4) enhanced uptake of 18F-fluorodeoxyglucose (FDG) by 18F-FDG-positron emission tomography may not distinguish between inflammation mediated by autoimmunity and that mediated by microorganism infection. Here we discuss the characteristics of these two forms of aortic aneurysm and the points of which we have to be aware before reaching a final diagnosis

Expressions of Vascular Endothelial Growth Factor (VEGF)-D and VEGF Receptor-3 in Colorectal Cancer: Relationship to Lymph Node Metastasis

Angiogenic factors play a major role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF)- D is a ligand for VEGF receptor-3 (VEGFR-3/Flt-4), which mainly expressed on the lymphatic endothelium. Recent experimental studies have shown that VEGF-D induces tumor lymphangiogenesis and promote metastatic spread of tumor cells via lymphatic vessels. However, the contribution of VEGFD to lymph node metastasis in human colorectal cancer is less understood. We therefore examined VEGF-D and VEGFR-3 expression in patients with colorectal cancer. Sections of formalin-fixed and paraffin-embedded specimens from 76 colorectal cancers were immunohistochemically stained for VEGF-D and VEGFR-3. Staining for VEGF-D was positive in the cytoplasm of tumor cells in 43 of 76 examined tumors (56.6%). Staining for VEGFR-3 was positive in endothelial cells in 38 (50.0%) tumors. Univariate analysis showed that both VEGF-D and VEGFR-3 expressions correlated significantly with lymph node metastasis, histological type and depth of tumor invasion. However, logistic regression analysis indicated that VEGF-D expression, but not that of VEGFR-3, was an independent predictor for lymph node metastasis. Our data suggest that VEGF-D plays an important role in lymph node metastasis in colorectal cancer

MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression

There have been few advances in the treatment of small-cell lung cancer (SCLC) because of the lack of targets. MCL1, a member of the anti-apoptotic BCL-2 family, may be a treatment target in several cancers, including SCLC. However, whether the expression profile of the anti-apoptotic BCL-2 family affects MCL1 inhibition strategy is unknown. A tissue microarray (TMA) was created from consecutive patients who were diagnosed with SCLC and had previously undergone surgery at Kyoto University Hospital (Kyoto, Japan) between 2001 and 2017. We used S63845, a MCL1 inhibitor, to assess the cytotoxic capacity in SCLC cell lines including a patient-derived cell line in vitro and in vivo. The combination of S63845 with navitoclax, a double BCL-XL/BCL-2 inhibitor, was also employed to examine the comprehensive inhibition of the anti-apoptotic BCL-2 family. Immunohistochemistry of a TMA from patients with surgically resected SCLC demonstrated high MCL1 expression with low BCL-XL and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1- and low BCL-XL-expressing SCLC cell lines. S63845 induced BAK-dependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BCL-XL and BCL-2 improved the cytotoxic activity of S63845 and its combination with navitoclax increased the anti-tumor cytotoxicity, the therapeutic range of S63845 with navitoclax was narrow in in vivo studies. Our study suggests MCL1 inhibition therapy be applied for high MCL1- and low BCL-XL-expressing SCLC patients

Elevated Expression of Poly(ADP-Ribose) Polymerase-1 is Associated with Liver Metastasis in Colorectal Cancer.

Activation of poly(ADP-ribose) polymerase-1 (PARP-1) and its subsequent cleavage are early markers of apoptosis. PARP-1 is associated with DNA repair and so chromosome stability, cell cycle regulation, as well as tumorigenesis. To investigate the role of PARP-1 expression in colorectal carcinoma and its metastasis of liver, we compared the expression of PARP-1 in primary colorectal cancers with (n=15) and without liver metastasis (n=17) using a semi-quantitative reverse transcription - polymerase chain reaction. We also examined the expressions of poly(ADP-ribose) (PAR) and p53 in these tumors by immunohistochemistry. A significantly higher PARP-1 mRNA expression was noted in tumors with liver metastasis than those without liver metastasis (p<0.01). Colorectal cancers positively stained for p53 exhibited significantly higher PARP-1 mRNA expression than p53-negative tumors (p<0.01). The PAR labeling index (LI) of tumors with metastasis (0.33 ﾂｱ 0.33) was not significantly different (p=0.35) from that of tumors without liver metastasis (0.38 ﾂｱ 0.19). p53-positive tumors tended to have higher PAR LI levels than p53-negative tumors (p=0.08). Our findings suggest that PARP-1 may contribute to liver metastasis due to its DNA repair activity, resulting in survival of the tumor cells with accumulation of metastaticrelated gene\u27s damages. Detailed analysis of PARP-1 may be useful in cancer research and/or cancer therapy

Nr5a1 suppression during the murine fetal period optimizes ovarian development by fine-tuning Notch signaling

The nuclear receptor NR5A1 is equally expressed and required for development of the gonadal primordia of both sexes, but, after sex determination, it is upregulated in XY testes and downregulated in XX ovaries. We have recently demonstrated, in mice, that this downregulation is mediated by forkhead box L2 (FOXL2) and hypothesized that adequate suppression of Nr5a1 is essential for normal ovarian development. Further, analysis of human patients with disorders/differences of sex development suggests that overexpression of NR5A1 can result in XX (ovo)testicular development. Here, we tested the role of Nr5a1 by overexpression in fetal gonads using a Wt1-BAC (bacterial artificial chromosome) transgene system. Enforced Nr5a1 expression compromised ovarian development in 46,XX mice, resulting in late-onset infertility, but did not induce (ovo)testis differentiation. The phenotype was similar to that of XX mice lacking Notch signaling. The expression level of Notch2 was significantly reduced in Nr5a1 transgenic mice, and the ovarian phenotype was almost completely rescued by in utero treatment with a NOTCH2 agonist. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by finetuning Notch signaling