No abstract

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-alpha in several types of cells. In the present study, we have shown that all the types of PDEIs, from type I- to V-specific and non-specific, suppress the production of TNF-alpha by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-alpha production by microglia at a very low concentration (1 microM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-alpha may play a critical role. Some PDEIs also suppressed interleukin-I (IL-I) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-alpha and induction of IL-10 were confirmed at the mRNA level by RT-PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).

ABSTRACT. Metastasis of malignant carotid body tumor to multiple bones was detected in a 13-year-old female Siberian husky dog. Radiographs exhibited an abnormal mass in the retropharyngeal site and osteolytic lesions in the vertebral bodies, spinous process, tibia, and ribs. At necropsy, multiple masses were observed in the bones as well as at the dorsal area of the retropharynx. Histologically, the tumor cells, arranged in sheets and clusters, had eosinophilic finely granular cytoplasm. Immunohistochemistry showed the tumor cells were positive for neuron-specific enolase and synaptophysin. Electron microscopy demonstrated a number of dense membrane-bound granules in the cytoplasm of the tumor cells. Based on these findings, this case was diagnosed as multiple bone metastases of a malignant carotid body tumor. Spinal cord damage induced by the tumor mass was the cause of the hind limb paralysis of the present dog. KEY WORDS: canine, carotid body tumor, osseous metastases.J. Vet. Med. Sci. 69(3): 297-299, 2007 Chemoreceptors including carotid body and aortic body play a role in regulation of oxygen, carbon, and hydrogen ion content of the blood [7]. Carotid body lies dorsal to the bifurcation of the common carotid artery [5] and carotid body tumors arise at the cranial area of the artery [2]. Carotid body tumors in dogs tend to be more malignant than aortic body tumors, and metastases are present in approximately 30% of the reported cases [3]. To the best of our knowledge, osseous metastases of carotid body tumors in dogs have not been reported in the literature. In this report, we describe a malignant carotid body tumor with multiple osseous metastases in a dog.A 13-year-old female Siberian husky dog was brought to the Medical Center Nishida Veterinary Clinic with a history of pain and lameness of the right hind limbs. During a period of approximately 3 months, clinical neurological abnormalities such as knuckling, astasia and loss of deep pain of both sides of hind limbs were progressed. Biochemistry and hematology showed aspartate aminotransferase 118 U/l, alkarine phosphatase 586 U/l, lactate dehydrogenase 514 U/l, lipase 299 U/l, C reactive protein 13 mg/dl. Radiographs exhibited an abnormal mass in the retropharyngeal site (Fig. 1) and osteolytic lesions in the vertebral bodies and spinous processes of 8th and 9th thoracic vertebrae (Fig. 2), proximal part of right tibia, and 2nd and 3rd ribs. Because of a poor prognosis, the dog was euthanatized by the administration of overdose of pentbarbital.At necropsy, a mass (4.4 × 4.0 × 3.2 cm) encapsulated by a thin fibrous connective tissue was observed attaching to the dorsal area of the retropharynx. On cut surface, the mass was hemorrhagic with abundant vascularity and consisted of white and red foci. Multiple white nodular masses were detected in the 8th thoracic vertebra, right 3rd, left 2nd, 3rd and 5th ribs, and right tibia. Osteolytic changes were dominant in the 8th thoracic vertebral body, where there was an extensive growth of the nodular masses to ...

Nitric oxide (NO) is considered to play a crucial role in the development of various pathological processes in the CNS, such as neuronal degeneration, inflammation and demyelination. In order to search for the agents which suppress NO production in the CNS, we examined the effects of one of the agents which elevate cyclic AMP production, phosphodiesterase inhibitors (PDEIs), on NO production by glial cells in vitro. All the types of PDEIs, from type I- to V-specific and non-specific, suppressed the production of NO by mouse microglia and astrocytes stimulated with lipopolysaccharide, in a dose-dependent manner. Suppression of inducible NO synthase by PDEIs was confirmed by the expression of mRNA by RT-PCR. Although it required 10 microM or higher concentration to effectively suppress NO production in vitro, certain combinations of three different PDEIs synergistically suppressed NO production by astrocytes at 1 microM which could be obtained in vivo at usual therapeutic doses. Similary, combinations of three PDEIs at 1 microM synergistically increased intracellular cAMP in astrocytes. The suppressive effects of PDEIs on NO production were abolished by addition of tumor necrosis factor alpha (TNFalpha). Thus, the main suppression mechanism of NO might be indirect through suppression of TNFalpha. Since some PDEIs are reported to pass through the blood-brain-barrier, the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis, human immunodeficiency virus-related neurological diseases and other neurodegenerative disorders in which NO may play a crucial role.

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-alpha in several types of cells. In the present study, we have shown that all the types of PDEIs, from type I- to V-specific and non-specific, suppress the production of TNF-alpha by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-alpha production by microglia at a very low concentration (1 microM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-alpha may play a critical role. Some PDEIs also suppressed interleukin-I (IL-I) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-alpha and induction of IL-10 were confirmed at the mRNA level by RT-PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).