moxidectin and Disease-Models--Animal

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor and cognitive deficits, the result of dopamine (DA)-depletion within the basal ganglia. Currently, DA replacement therapy in the form of Sinemet (L-DOPA plus Carbidopa) provides symptomatic motor benefits and remains the "gold standard" for treatment. Several pharmacological approaches can enhance DA neurotransmission including the administration of DA receptor agonists, the inhibition of DA metabolism, and enhancing pre-synaptic DA release. DA neurotransmission is regulated by several receptor subtypes including signaling through the purinergic system. P2 × 4 receptors (P2 × 4Rs) are a class of cation-permeable ligand-gated ion channels activated by the synaptic release of extracellular adenosine 5'-triphosphate (ATP). P2 × 4Rs are expressed throughout the central nervous system including the dopaminergic circuitry of the substantia nigra, basal ganglia, and related reward networks. Previous studies have demonstrated that P2 × 4Rs can modulate several DA-dependent characteristics including motor, cognitive, and reward behaviors. Ivermectin (IVM) and moxidectin (MOX) are two macrocyclic lactones that can potentiate P2 × 4Rs. In this study, we sought to investigate the role of P2 × 4Rs in mediating DA neurotransmission by exploring their impact on DA-dependent behavior, specifically rotation frequency in the unilateral 6-hydroxydopamine-lesioned mouse model of DA-depletion. While we did not observe any differences in the degree of lesioning based on immunostaining for tyrosine hydroxylase between sexes, male mice displayed a greater number of rotations with L-DOPA compared to female mice. In contrast, we observed that IVM plus L-DOPA increased the number of rotations (per 10 min) in female, but not male mice. These findings highlight the potential role of pharmacologically targeting the purinergic receptor system in modulating DA neurotransmission as well as the importance of sex differences impacting outcome measures.

Topics: Amphetamine; Animals; Central Nervous System Stimulants; Disease Models, Animal; Female; Ivermectin; Macrolides; Male; Medial Forebrain Bundle; Mice, Inbred C57BL; Movement; Oxidopamine; Parkinson Disease

Substantial data indicate that an imbalance in gut microbiome (GM), also referred to as dysbiosis, may play an important role in depression. Moreover, drugs that normalize GM can result in an antidepressant-like effect. It was reported recently that moxidectin (MOX), an antiparasitic drug commonly used in veterinary medicine, has a positive influence on microbiota implicated in mood regulation. We undertook this study to determine whether MOX would actually show antidepressant-like properties in an animal model of depression and whether it would affect the hippocampal and frontal cortex levels of brain-derived neurotrophic factor (BDNF) or tumor necrosis factor (TNF)-alpha, peptides that have been implicated in pathogenesis of depression and effectiveness of various antidepressants. Adult male Wistar-Kyoto rats, a putative animal model of depression, were treated with a single dose of MOX (2.5 mg/kg, i.p.) and their performance in the open field locomotor activity (OFLA) as well as in the forced swim test (FST) was evaluated at 24 h, one week and two weeks after the single injection. A separate group of rats were injected with 2.5 mg/kg MOX and sacrificed 24 h later for neurochemical evaluations. MOX resulted in a decrease in immobility score after 24 h, whereas OFLA was not affected. Concomitant with the 24 h behavioral effects, the levels of hippocampal and frontal cortical BDNF were significantly increased, whereas the levels of TNF-alpha in both these areas were significantly decreased. The decrease in immobility scores was still evident after one week, but not 2 weeks of rest. These results indicate long lasting antidepressant effects of a single MOX dose and suggest potential utility of this drug in treatment-resistant depression.

Topics: Animals; Brain-Derived Neurotrophic Factor; Depression; Depressive Disorder; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Hippocampus; Macrolides; Male; Prefrontal Cortex; Rats; Rats, Inbred WKY; Tumor Necrosis Factor-alpha

Topics: Acaricides; Administration, Oral; Animals; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Repositioning; Humans; Macrolides; Scabies

This study investigated the efficacy and safety of an imidacloprid 10 %/moxidectin 2.5 % spot-on combination (Advocate®, Advantage® Multi, Bayer) against immature and mature stages of Spirocerca lupi in experimentally infected dogs. 24 dogs were allocated to 3 groups and infected with approximately 10 L3 larvae of S. lupi orally on study day (SD) +2, +14, +28 and +42. Group 1 remained as untreated control group. Group 2 dogs were treated on SD –28, 0, and thereafter monthly until Day 280 (12 treatments). Group 3 dogs were treated weekly on 19 occasions starting on SD +170. The dosage for all treatments was the licensed dose of 10–25 mg imidacloprid/2.5–6.25 mg moxidectin per kg body weight. All dogs were examined on SD +169 or +176 by endoscopy. Group 3 dogs were additionally examined approximately every two weeks up to Day 296. On Day +308 or +310, all dogs were necropsied to recover S. lupi worms and to quantify lesions in the thoracic aorta and oesophagus. Dogs in the control group were adequately infected with S. lupi, demonstrated by the extensive damage to the thoracic aorta, the nodules in the oesophagus and the large numbers of worms recovered. In total 144 worms were collected (geometric mean of 16.8 worms per dog). Dogs in group 2 had no or very slight damage to the thoracic aorta and no nodules or worms in the oesophagus, indicating 100 % efficacy of the monthly treatments. Dogs in group 3 were also adequately infected, showing nodules in the oesophagus before initiation of weekly treatment, and at necropsy extensive damage was seen in the thoracic aorta. After treatment, three dogs of 8 still had a few nodules and in total three worms (GM of 0.25 per dog) were recovered, demonstrating an efficacy of 98.5 % against adult S. lupi. All dogs tolerated the treatment well and no treatment- related adverse events occurred.

Topics: Adult; Animals; Anthelmintics; Aorta, Thoracic; Disease Models, Animal; Dogs; Drug Combinations; Endoscopy; Esophagus; Humans; Imidazoles; Macrolides; Neonicotinoids; Nitro Compounds; Spirurida Infections; Thelazioidea; Treatment Outcome

Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.

Topics: Animals; Anti-Infective Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Digoxin; Disease Models, Animal; Dog Diseases; Dogs; Domperidone; Female; Ivermectin; Macrolides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis, Insertional

The aim of this comparative study was to investigate the development of clinical signs and accompanying haematological, coproscopic and pathological findings as a basis for the monitoring of health condition of Angiostrongylus vasorum infected dogs. Six beagles were orally inoculated with 50 (n=3) or 500 (n=3) A. vasorum third stage larvae (L3) obtained from experimentally infected Biomphalaria glabrata snails. Two dogs were treated with moxidectin/imidacloprid spot-on solution and two further dogs with an oral experimental compound 92 days post infection (dpi), and were necropsied 166 dpi. Two untreated control dogs were necropsied 97 dpi. Prepatency was 47-49 days. Dogs inoculated with 500 L3 exhibited earlier (from 42 dpi) and more severe respiratory signs. Clinical signs resolved 12 days after treatment and larval excretion stopped within 20 days in all four treated dogs. Upon necropsy, 10 and 170 adult worms were recovered from the untreated dogs inoculated with 50 and 500 L3, respectively. Adult worms were also found in two treated dogs, in the absence of L1 or eggs. Despite heavy A. vasorum infection load and severe pulmonary changes including vascular thrombosis, only mild haematological changes were observed. Eosinophilia was absent but the presence of plasma cells was observed. Neutrophilic leucocytes showed a transient increase but only after treatment. Signs for coagulopathies were slight; nevertheless coagulation parameters were inoculation dose dependent. Ten weeks after treatment pulmonary fibrosis was still present. Infections starting from 50 L3 of A. vasorum had a massive impact on lung tissues and therefore on the health of affected dogs, particularly after prepatency, although only mild haematological abnormalities were evident.

Topics: Angiostrongylus; Animals; Anthelmintics; Disease Models, Animal; Dog Diseases; Dogs; Eosinophilia; Feces; Imidazoles; Lung; Macrolides; Neonicotinoids; Neutrophils; Nitro Compounds; Strongylida Infections

Third-stage larvae of the major human and canine Ancylostoma hookworm species have the capacity to undergo developmental arrest in the somatic tissues of an infected host. Arrested larvae reactivate at opportune periods such as pregnancy, which results in the transmammary transmission of infection to the nursing neonates. Using murine paratenic hosts to focus specifically on tissue-arrested stages of Ancylostoma caninum, the present study found that neither recommended nor elevated doses of commonly used anthelmintics were effective in eliminating latent infections at the accepted standard of greater than 90% reduction in parasite burden. Of the drugs tested, i.e., pyrantel, fenbendazole, ivermectin, and milbemycin, ivermectin was the most effective and engendered an 80% reduction in the burden of tissue-arrested A. caninum larvae but only if administered repeatedly or at elevated doses. Studies in 2 inbred mouse strains, BALB/c (H-2b) and C57BL/6 (H-2d), that typically display divergent immune responses to various infections showed no significant differences in the efficacies of the drugs tested. The results of this study indicate that there is still a need for effective strategies of eradicating latent infections with tissue-arrested hookworm larvae.

Topics: Ancylostomiasis; Animals; Anti-Bacterial Agents; Antinematodal Agents; Disease Models, Animal; Dogs; Female; Fenbendazole; Humans; Ivermectin; Macrolides; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pyrantel Pamoate; Random Allocation

A new anthelmintic assay is described which uses immunosuppressed (60 ppm hydrocortisone acetate in diet) rats infected with the nematode Trichostrongylus colubriformis. Immunosuppressed rats were infected with 1500 T. colubriformis larvae, treated either orally or subcutaneously on Day 14 post-infection and necropsied 4 days after treatment. The worm counts in immunosuppressed control animals averaged 775 worms per rat. A range of benzimidazoles, levamisole hydrochloride, morantel tartrate, 22,23-dihydroavermectin B1a and alpha-milbemycin have been evaluated in the assay. The ED95 values obtained indicate that rats infected with T. colubriformis provide a highly predictive model for assaying the activity of experimental drugs in vivo prior to studies in ruminants.

Topics: Animals; Anthelmintics; Anti-Bacterial Agents; Benzimidazoles; Disease Models, Animal; Feces; Immunosuppression Therapy; Ivermectin; Levamisole; Macrolides; Male; Morantel; Parasite Egg Count; Rats; Ruminants; Trichostrongylosis