Striosomal opioid receptors

The opioid peptide receptors consist of three major subclasses, namely, μ, δ, and κ (MOR, DOR, and KOR, respectively). They are involved in the regulation of striatal dopamine functions, and increased opioid transmissions are thought to play a compensatory role in altered functions of the basal ganglia in Parkinson's disease (PD). In this study, we used an immunohistochemistry with tyramide signal amplification (TSA) protocols to determine the distributional patterns of opioid receptors in the striosome-matrix systems of the rat striatum. As a most striking feature of striatal opioid anatomy, MORs are highly enriched in the striosomes and subcallosal streak. We also found that DORs are localized in a mosaic pattern in the dorsal striatum (caudate-putamen), with heightened labeling for DOR in the striosomes relative to the matrix compartment. In the 6-hydroxydopamine-lesioned rat model of PD, lesions of the nigrostriatal pathways caused a significant reduction of striatal labeling for both the MOR and DOR in the striosomes, but not in the matrix compartment. Our results suggest that the activities of the striosome and matrix compartments are differentially regulated by the opioid signals involving the MORs and DORs, and that the striosomes may be more responsive to opioid peptides (e.g., enkephalin) than the matrix compartment. Based on a model in which the striosome compartment regulates the striatal activity, we propose a potent compensatory role of striosomal opioid signaling under the conditions of the striatal dopamine depletion that occurs in PD

Central effects of botulinum toxins

Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action.We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 to 13.6U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6U, and this muscle flaccidity increased until the fourth day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved synaptosomal-associated protein of 25 kDa (SNAP-25) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications

Striatal Cdk5-pTyr15

Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl) is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5) and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15) is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571), a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum

Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice

Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl) is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5) and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15) is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571), a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum

Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports

Abstract Background Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1–3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. Method In this study we report the clinical courses of three cases with HDGC from a single Japanese family. Results The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. Conclusion It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries