Does a therapeutical dose of ivermectin impairs testicular homeostasis of rats via excessive apoptosis?

Ivermectin is a medication used to treat parasite infestations in humans and in veterinary medicine. Previously we showed that therapeutical doses of ivermectin impaired spermatogenesis and spermiogenesis in adult rats. The present study was proposed to understand the pathophysiological mechanism that triggered these impairments induced by ivermectin. It was a particular objective to study if ivermectin induced excessive apoptosis. Adult rats were treated with a therapeutical dose of ivermectin (subcutaneously). Their testis was evaluated for the expression of caspase-3 (a marker of apoptosis), using immunohistochemistry techniques. Results revealed that ivermectin treatment increased the expression of caspase-3 (labeled seminiferous tubules and strongly labeled tubules), as well as increased the number of tubules that presented labeled cells in the tubular lumen, compared to the data of the control group. In conclusion, a therapeutical dose of ivermectin induced expressive apoptosis in cells of the seminiferous tubules of rats, affecting the testicular natural homeostasis process, which resulted in the spermatogenesis and spermiogenesis impairments previously reported.

Ivermectin prevents stress-induced testicular damage in juvenile rats.

Ivermectin is a popular antiparasitic drug used in veterinary and human medicine. Studies by our group have shown that therapeutic doses of ivermectin induce some brain and behavioral impairments, especially in the reproductive sphere. So far, the studies were focused in adulthood. Considering that juveniles are more susceptible to drugs during developmental stages and both farm/domestic animals and humans have been medicated with ivermectin in youth, it is necessary to evaluate the possible harm effects in youth. The stress variable is also important, as it potentially influences the effects produced by ivermectin. Therefore, the objective of this study was to evaluate morphofunctional and hormonal reproductive aspects of juvenile rats exposed to ivermectin and/or stressed. Prepubertal male rats were treated with 0.2 or 1.0 mg/kg of ivermectin (a therapeutic dose and a higher dose, respectively). Rats were also submitted to a restraint stress session. The testis morphology and histology were analyzed and plasma testosterone levels were measured. The two doses of ivermectin did not induce a biologically relevant effect on testis and testosterone levels of rats. However, restraint stress impaired macroscopic and microscopic morphometric and stereological parameters, as well as the histology of the testis: it increased the relative testis weight, the tubular diameter, the tubular luminal diameter, and the tubular cellular index, and injured the interstitial area. Previous treatment of juvenile rats with ivermectin prevented most of the stress-induced testes injuries. In conclusion, in addition to be a remarkable antiparasitic agent, ivermectin prevented stress-induced testes injuries in juvenile rats.

Luffa operculata fruit aqueous extract induces motor impairments, anxiety-like behavior, and testis damage in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn., Cucurbitaceae (buchinha-do-norte), aqueous extract (EBN) is popularly used to relieve symptoms of sinusitis and as abortive. AIM OF THE STUDY: As neurotoxicity and toxicity studies on the male reproductive system are scarce, the present study aimed at quantitatively addressing the question. MATERIALS AND METHODS: Male adult rats were observed in the open field (OF) and in the light-dark box test (LDB) to evaluate locomotion and anxiety. Macroscopical and microscopical alterations on the rats' testes were also studied. The rats were divided into two groups, control (GC) and experimental (GE). GE received 1.0 mg/kg per day of EBN, orally, for five consecutive days, whereas GC received water. On the 6th day, each animal was evaluated in OF and in LDB for 3 min in each apparatus. After that, the left testicles were studied. RESULTS: In the OF, GE showed decreased locomotion, increased immobility time and decreased grooming and remained for less time in the center of the apparatus. In LDB, GE showed significant difficulty in moving into the light side of the device and remained longer in the dark side, exhibiting less displacement on both sides and less transitions between sides. Testicle weights, relative weights, testicular volume, cranial-caudal and lateral-lateral axes presented an increase in relation to the GC. Microscopic changes were observed in parenchyma, lumen and diameter of seminiferous tubules. Leydig cell numbers were decreased in GE. CONCLUSIONS: The administration of EBN induced anxiety-like behavior, impaired locomotion and altered the testes morphology of rats.

Ivermectin acute administration impaired the spermatogenesis and spermiogenesis of adult rats.

Ivermectin (IVM) is an antiparasitic agent widely used in agricultural, domestic animals and in human clinical practice. In the present study, the temporal effects of therapeutic doses of IVM in the morphometric and histological assessment of testis were studied to verify if IVM acute administration impaired the spermatogenesis and spermiogenesis of adult rats, if these effects are reversible. The testosterone levels and the plasmatic IVM levels were assessed. The results show: 1) IVM acute exposure, mainly in the higher dose, reduced the testicular volume, the tubular diameter and the germinal epithelium height; 2) no interferences on Leydig cells frequency; 3) histological studies show that tubular sections containing several histological changes indicative of spermatogenesis interruption, such as disorganization of germinal epithelium, vacuolar degeneration of the germ cells and sloughing of cells into the tubular lumen; 4) no differences in testosterone levels; 5) The IVM plasmatic levels were significantly reduced at 72h after the 0.2mg/kg. It was concluded that acute IVM impaired the spermatogenesis and spermiogenesis of rats. Probably these effects were not consequence of IVM at the Leydig cells because no effects were observed at this level. Finally, our results suggest that some testicular effects are reversible and correlated with the plasmatic levels of IVM.