Nicotine has a therapeutic window of effectiveness in a Drosophila melanogaster model of Parkinson’s disease

Strong epidemiological evidence and studies in models of Parkinson’s disease (PD) suggest that nicotine may be therapeutically beneficial in PD patients. However, a number of clinical trials utilizing nicotine in PD patients have had mixed results, indicating that either nicotine is not beneficial in PD patients, or an important aspect of nicotine therapy was absent. Here we show that continuous early nicotine administration improves both climbing and flight deficiencies present in homozygous park25 mutant PD model Drosophila melanogaster. Using a new climbing assay, we identify several climbing deficiencies in this PD model that are improved or rescued by nicotine treatment. Amongst these benefits, it appears that nicotine improves the ability of the park25 flies to descend the climbing vial by being able to climb down more. Importantly, we show that in order for nicotine benefits on climbing and flight to happen, nicotine administration must occur in a discrete time frame following adult fly eclosure: within one day for climbing or five days for flight. This therapeutic window of nicotine administration may help to explain its lack of efficacy in human clinical trials, suggesting a need to test earlier nicotine therapy in PD patients.

STRUCTURE-ACTIVITY STUDIES ON ANALOGUES OF 4-METHYLGUAIACOL, A CATTLE ANAL ODOUR CONSTITUENT REPELLENT TO THE BROWN EAR TICK (Rhipicephalus appendiculatus)

Previously, 4-methylguaiacol, a major constituent of cattle anal odour, was found to have a high repellence on Rhipicephalus appendiculatus. In the present study, 10 structural analogues of the phenol were tested for repellence against R. appendiculatus in order to assess the effects of (i) absence or presence of the 4-alkyl group of varying length, (ii) inclusion of a double bond in the 4-alkyl chain, (iii) linking the two phenolic oxygen in a methylenedioxy bridge, (iv) replacement of the OCH3 with CH3 and inclusion of another CH3 at position 6, and (v) presence of an additional OCH3 group at position 6. The analogues comprised of 2-methoxyphenol (guaiacol), 4-ethyl-2- methoxyphenol, 4-propyl-2-methoxyphenol, 4-allyl-2-methoxyphenol (eugenol), 3,4-methylenedioxytoluene, 2,4- dimethylphenol, 4-ethyl-2-methylphenol, 2,4,6-trimethylphenol, 4-propyl-2,6-dimethoxy-phenol and 4-allyl-2,6- dimethoxyphenol, which were compared at different doses in a two-choice climbing assay set up. Each analogue showed either increased or reduced repellence compared with 4-methylguaiacol. The structural feature that was associated with the highest repellence was 4-propyl moiety in the guaiacol unit (RD75 = 0.031 for 4-propyl-2- methoxyphenol; that of 4-methylguaiacol = 0.564). Effects of blending selected analogues with high repellence were also compared. However, none of the blends showed incremental increase in repellence compared with that of 4- propyl-2-methoxyphenol. We are currently evaluating the effects of controlled release of the compound at different sites on cattle on the behavior and success of R. appendiculatus to locate their predilection feeding site.

Repellent Activities of Essential Oils of Some Plants Used Traditionally to Control the Brown Ear Tick,Rhipicephalus appendiculatus

Essential oils of eight plants, selected after an ethnobotanical survey conducted in Bukusu community in Bungoma County, western Kenya (Tagetes minuta, Tithonia diversifolia, Juniperus procera, Solanecio mannii, Senna didymobotrya, Lantana camara, Securidaca longepedunculata, andHoslundia opposita), were initially screened (at two doses) for their repellence against brown ear tick,Rhipicephalus appendiculatus, using a dual-choice climbing assay. The oils ofT. minutaandT. diversifoliawere then selected for more detailed study. Dose-response evaluations of these oils showed thatT. minutaoil was more repellent (RD50= 0.0021 mg) than that ofT. diversifolia(RD50= 0.263 mg). Gas chromatography-linked mass spectrometric (GC-MS) analyses showed different compositions of the two oils.T. minutaoil is comprised mainly ofcis-ocimene (43.78%), dihydrotagetone (16.71%), piperitenone (10.15%),trans-tagetone (8.67%), 3,9-epoxy-p-mentha-1,8(10)diene (6.47%),β-ocimene (3.25%), andcis-tagetone (1.95%), whereasT. diversifoliaoil is comprised mainly ofα-pinene (63.64%),β-pinene (15.00%), isocaryophyllene (7.62%), nerolidol (3.70%), 1-tridecanol (1.75%), limonene (1.52%), and sabinene (1.00%). The results provide scientific rationale for traditional use of raw products of these plants in controlling livestock ticks by the Bukusu community and lay down some groundwork for exploiting partially refined products such as essential oils of these plants in protecting cattle against infestations withR. appendiculatus.