Quinolone antimicrobial agents induce two types of histological changes in the articular cartilage of synovial joints in immature, but not mature, laboratory animals. The first is cavity formation in the middle zone of the articular cartilage in animals of all species examined so far, and this can be induced by a single or several daily doses. The second is osteochondrotic lesions in the caudal femoral condyles of rats when subchronic or chronic treatment is started at a juvenile age, but there seems to be only one reference for this effect. The development process of cavity formation is as follows. Degeneration and necrosis of chondrocytes are first observed, and the surrounding matrix becomes edematous with demasked collagen fibrils and decreased safranin O stainability. A flat cleft or cavity is then formed in the edematous cartilage, and erosion is sometimes produced by detachment of the cavity outer wall. The potency of quinolones to form chelate complexes with Mg²⁺ is discussed as causal for cavity formation. This could lead to Mg²⁺ deficiency in the cartilage, resulting in integrin alteration and further radical formation that can finally induce cartilage lesions. On the other hand, an early change of osteochondrosis is a thickened middle zone of the articular cartilage with a thinned deep zone. The thickened cartilage protrudes into the epiphysis and prevents age-dependent thinning of the cartilage. In advanced cases, fissures are formed in the bottom of the thickened cartilage, and extension of the fissures to the cartilage surface induces detachment of the cartilage, subchondral bone necrosis and fibrotic lesions in the marrow space. The lesions are considered to be caused by quinolone-induced inhibition of the differentiation of chondrocytes in the middle zone into those in the deep zone. For chondrotoxicity in juvenile animals, the pediatric use of quinolones is generally contraindicated, but whether or not chondrotoxicity could really occur in pediatric patients is still controversial.

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Seventy years ago it was discovered that glutamate plays a central role in brain metabolism and is abundant in the brain. Glutamate was then found to be the principal excitatory neurotransmitter in the brain. As stated in the first article of this series, there are three families of ionotropic receptors with intrinsic cation permeable channels: N-methyl-D-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate [Ka]. Among these there are three groups of metabotropic, G protein-coupled glutamate receptors [mGluR] that modify neuronal and glial excitability through G protein subunits acting on membrane ion channels and second messengers such as diacylglycerol and cAMP. There are also two glial glutamate transporters and three neuronal transporters in the brain. Although glutamate is the most abundant amino acid in the diet, there is no evidence for brain damage in humans resulting from dietary glutamate. However, a Ka analog, domoate, is sometimes ingested accidentally in blue mussels; this potent toxin causes limbic seizures, which can lead to hippocampal and related pathology and amnesia. Endogenous glutamate may contribute to the brain damage occurring acutely after status epilepticus, cerebral ischemia or traumatic brain injury by activating NMDA, AMPA or mGluR₁ receptors. Glutamate may also contribute to chronic neurodegeneration in such disorders as amyotrophic lateral sclerosis and Huntington's disease. In animal models of cerebral ischemia and traumatic brain injury, NMDA and AMPA receptor antagonists protect against acute brain damage and delayed behavioral deficits. Other clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis. In this second part of this review, we will explore those diseases in which the pathophysiology and pathology are associated, in part, with the glutamate system.

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The effect of rat albumin (RALB) on D-galactosamine (GalN) hepatotoxicity was investigated in male Crl:CD(SD) rats aged 6 weeks. The animals were divided into control, RALB, GalN, and RALB + GalN groups. GalN (800 mg/kg) was intraperitoneally administered immediately after an intravenous injection of RALB (100 mg/kg). The animals were euthanized 6 or 24 h later and subjected to laboratory investigations and histological examinations of the liver. Furthermore, in order to determine the contributing factors of the effect on the hepatotoxicity, intra- and inter-group comparisons were made between liver-injured and normal animals for parameters showing marked fluctuations at 6 h post-dosing. As a result, RALB induced fluctuations in many parameters, but no histological changes were observed in the liver at both 6 and 24 h. GalN induced mild or moderate hepatocyte necrosis (necrosis and/or apoptosis of hepatocytes) at 6 and 24 h, respectively, accompanied by increases in the serum ALT and AST levels. Concurrent administration of RALB with GalN markedly aggravated the GalN-induced hepatotoxicity, as shown by severe hepatocyte necrosis accompanied by further increases in the serum ALT, AST, and T-BIL levels in the surviving animals at 6 and 24 h, and by very severe hepatocyte necrosis with congestion in the dead animals. Moreover, serum tumor necrosis factor-α (TNF- α) level was also increased at 6 h in the RALB + GalN group, but not in the RALB or GalN alone groups. In conclusion, RALB was shown to aggravate GalN hepatotoxicity in rats, and the increased serum TNF-α level is considered to be a contributing factor of the aggravation.

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N-methyl-D-aspartate (NMDA) receptors constitute one of the three major classes of ionotropic glutamate receptors. We found neuronal necrosis in the brain of one out of four beagles exposed to an NMDA receptor antagonist. The lesions were characterized by shrunken cell bodies with intense cytoplasmic eosinophilia and pyknotic nuclei, and the affected cells were specifically positive for Fluoro-Jade B staining, which has great affinity for degenerating neurons. Bilaterally symmetrical lesions were observed primarily in the dentate gyrus, hippocampus, subiculum and entorhinal cortex. The present case suggests that NMDA receptor antagonism, possibly by altering synaptic transmission via receptors to glutamate within the affected regions, might lead to neuronal necrosis in the canine brain. Other possible pathogeneses include the encephalic ischemic condition associated with seizure activity.

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A mixed epithelial and stromal tumor (MEST) of the kidney was found in a 22-month-old female Marshall beagle. Histopathologically, this lesion was well demarcated and was composed of a mixture of epithelial and stromal elements. The epithelial elements, which contained columnar or ciliated columnar epithelia, had cystic and tubular growth patterns. The tubular lumina contained eosinophilic materials, which were positive for periodic acid Schiff and alcian blue (pH 2.5). Immunohistochemically, the epithelia were positively stained with proliferative cell nuclear antigen (PCNA) and showed co-expression of cytokeratin and vimentin. Morphologically, these proliferative ductal structures were suggestive of a primitive duct arising from the mesonephric or paramesonephric tubule. The stromal elements were characterized by proliferation of spindle cells embedded in a collagen-rich eosinophilic matrix. Additionally, stromal cells were positive for PCNA, vimentin and muscle markers (α-smooth muscle actin and desmin). Therefore, this lesion was ultimately diagnosed as a MEST of the kidney.

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In a study to collect background data using c-Ha-ras transgenic mice (rasH2 mice), epithelial proliferative lesions were observed in the nasal cavities of the animals with or without administration of a single intraperitoneal dose of N-methyl-N-nitrosourea (MNU). These proliferative lesions occurred most frequently in the ventral meatus of the incisive papilla (nasal cavity in the specimen). Most of the proliferative lesions were a polypoid or papillary form consisting mainly of an epithelium resembling a squamous epithelium. In addition, administration of MNU tended to increase the incidence of proliferative lesions. Therefore, in carcinogenicity studies using rasH2 mice, we may come across epithelial proliferative lesions in the nasal cavity.

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