Cetirizine and thalidomide synergistically inhibit mammary tumorigenesis and angiogenesis in 7,12-dimethylbenz(a)anthracene-treated rats.

OBJECTIVE: Cetirizine (CET) and thalidomide (THA) have been previously found to influence angiogenesis. The present study aimed to assess the ability of these drugs to influence mammary carcinogenesis in rats. MATERIALS AND METHODS: Sixty Sprague-Dawley female rats, aged 8 weeks, received 15 mg of 7,12-dimethylbenz(a)anthracene (DMBA) intragastrically. CET and THA (1.0 and 3.0 mg/kg, respectively) were administered orally for 118 days after DMBA administration. At the end of the treatment period, mammary tumors were counted and weighed, and their morphology was analyzed using light microscopy. In tumor tissue, proliferation and apoptotic indices and microvessel density were determined using immunohistochemical techniques; the levels of angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, were measured by western blotting. RESULTS: CET and THA, administered separately, failed to influence tumor formation and angiogenesis. In contrast, the drug combination decreased latency to first tumor (significant difference from vehicle-treated control and groups that received either drug alone, P<0.01) and significantly lowered tumor number per rat, number of malignant tumors per rat, tumor burden, and tumor number per tumor-bearing animal (P<0.05 or <0.01). In tissue of malignant tumors, the drug combination decreased the number of proliferating cells, microvessel density, and levels of vascular endothelial growth factor and basic fibroblast growth factor and stimulated apoptosis (difference from all other groups, P<0.01). CONCLUSION: It was shown for the first time that H1-antagonist and THA synergistically inhibit DMBA-induced mammary carcinogenesis; this effect was associated with a decrease in tumor angiogenesis. Further study of the anticancer and antiangiogenic activity of the combination may provide a new approach to breast cancer treatment.

Brain sites mediating cyclosomatostatin-induced catalepsy in Wistar rats: A specific role for the nigrostriatal system and locus coeruleus.

A decrease in somatostatin activity is observed in the Parkinsonian brain. In recent experiments on rats, we simulated this abnormality by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin. The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease. The neuroanatomical substrates mediating the catalepsy-inducing effect of cyclosomatostatin are unknown. To clarify this issue, we assessed here the action of cyclosomatostatin injected into the substantia nigra pars compacta (SNc), dorsal striatum (DS), locus coeruleus (LC), pedunculopontine tegmental nucleus (PPTg), and inferior colliculus (IC). The experiments were conducted with male Wistar rats of 270-290 g bw, catalepsy was evaluated by using the bar test. The injections into the PPTg and IC were without effect whereas the intra-SNc, intra-DS, and intra-LC administrations produced distinct cataleptic response. Thus, it was shown for the first time that the LC is a brain center capable of causing catalepsy. These data provide new insights into the neuroanatomical organization of the catalepsy-initiating mechanism and suggest the LC representing a potential target for therapeutic manipulations of extrapyramidal dysfunctions.

Coadministration of bicuculline and NMDA induces paraplegia in the rat.

Motor neurons (MNs) of an adult rat are normally insensitive to the neurotoxic action of NMDA. Meanwhile, the experiments in non-motor neurons showed that sensitivity to NMDA can be increased by bicuculline, an antagonist at GABA(A) receptors. The aim of the present work was to examine whether bicuculline would produce such an effect in the adult MNs. In adult Wistar rats, intrathecal injection of bicuculline and NMDA individually failed to affect motor activity of the extremities. In contrast, bicuculline-NMDA combination dose-dependently impaired hindlimb functions. At the 9th day after injections of the combination, a paraplegia with persistent bilateral spastic extension developed in all animals. Light microscopic assessment showed that the development of the motor deficit is associated with pathological changes in spinal motor neurons (swelling, accumulation of the Nissl substance near nucleus, hyperchromatosis, shrinkage, and chromatolysis), mainly in the lumbar ventral horns. Additionally, distinct abnormalities were observed in the white matter of the lumbar cords. The bicuculline-NMDA combination induced a loss of spinal cord MNs while sparing the dorsal horn neurons. The effects of the combination were reversed by muscimol, a GABA(A) agonist. Thus, an inhibition of GABA(A)ergic processes can induce NMDA sensitivity in adult MNs. The present data may provide new insights into the mechanism of motor disorders in amyotrophic lateral sclerosis and other states wherein the combination of glutamatergic overstimulation and GABA(A)ergic understimulation takes place.