dextromethorphan and Parkinson-Disease--Secondary

This study investigated the effect of dextromethorphan (DXM) against Parkinson's disease (PD) in rats and explored the association between DXM dose and PD risk in elderly patients 65 years and older using a population-based database. The PD rat model (Sprague Dawley rats) was induced by injecting 6-hydroxydopamine (6-OHDA) into the unilateral medial forebrain bundle of the rat brain. DXM (20 mg/kg) was administered intraperitoneally twice daily from 7 days before the appearance of a 6-OHDA lesion to 28 days after the lesion appeared. The availability of dopamine transporter (DAT) and serotonin transporter (SERT) in the striatum of the rat brain was measured using positron emission tomography. The apomorphine-induced rotation test was performed to study the hypersensitivity of the brain regions with lesions. This animal study demonstrated that DXM significantly attenuated 6-OHDA-induced DAT and SERT loss, correlating to rotational behaviors. The population-based human study analyzed the data from the Taiwan Longitudinal Health Insurance Database 2005 between January 2005 and December 2013 and then used the DXM dose-response curve to investigate the trend of its protective effect against PD. In the human study, low cumulative doses of DXM may potentially achieve a protective effect for PD; however, high cumulative doses seem to be a risk for PD.

Topics: Aged; Aged, 80 and over; Animals; Behavior Observation Techniques; Behavior, Animal; Case-Control Studies; Corpus Striatum; Dextromethorphan; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; Female; Humans; Male; Oxidopamine; Parkinson Disease; Parkinson Disease, Secondary; Positron-Emission Tomography; Protective Agents; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins; Taiwan; X-Ray Microtomography

The neuroprotective agent 3-hydroxymorphinan (3-HM) is a well-documented and highly safe therapeutic intervention for the inflammatory-related effects of Parkinson's disease (PD). However, the bioavailability of 3-HM is very low due to the rapid first-pass metabolism of the phenolic moiety. In the present study, we sought to improve the metabolic stability and overall pharmacokinetic profile of 3-HM. Based on an iterative design process that a suitably arranged heterocycle with an NH group would serve as the metabolically stable isostere of the phenolic group, we designed and synthesized two analogues of 3-HM. Benzimidazolone compound 8 (imidazolone-morphinan) was comparable in activity to 3-HM against lipopolysaccharide (LPS)-induced inflammatory responses in microglial BV2 cells and in vivo animal experiments (MPTP-induced PD mouse model). Moreover, the in vitro study showed that imidazolone-morphinan was non-toxic to microglia, indicating its high safety. Considering the favourable and unique preclinical profiles, compound 8 was nominated as a candidate for further clinical development.

Topics: Animals; Antiparkinson Agents; Cell Line; Dextromethorphan; Drug Evaluation, Preclinical; Male; Mice; Microglia; Parkinson Disease, Secondary

The effects of acute and chronic dextromethorphan on levodopa-induced motor response alterations have been studied in rats with unilateral lesion of nigrostriatal pathway induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a 6-OHDA injection (8 microg) into the left medial forebrain bundle. To validate the effect of acute dextromethorphan administration, groups of rats were treated with levodopa (25 mg/kg, twice daily) for 22 days. On day 23, animals received dextromethorphan (20, 30 or 40 mg/kg) immediately before levodopa. In a second set of experiments, lesioned rats were concomitantly treated with levodopa plus dextromethorphan (20, 30 or 40 mg/kg, twice at day) for 22 consecutive days in order to investigate the potential effect of chronic dextromethorphan administration in preventing the decrease in the duration of motor response. As expected, the duration of the motor response to levodopa had significantly decreased by the 22nd day of levodopa in each group of treatment. Acute administration of dextromethorphan on day 23 reversed the reduction in the duration of the levodopa response only when administered at the lowest dose used in the present study (20 mg/kg) (p<0.05). Chronic administration of dextromethorphan concomitant to levodopa did not prevent levodopa effect showing a significant decrease on motor response duration (124+/-4 on day 1 vs. 88+/-16 on day 22, p<0.05, 30 mg/kg, twice a day). Our results indicate that in parkinsonian rats dextromethorphan is not a useful drug to prevent levodopa-induced motor alterations, however, low doses of dextromethorphan may be beneficial to reverse these alterations in motor response.

Topics: Animals; Antiparkinson Agents; Dextromethorphan; Disease Models, Animal; Excitatory Amino Acid Antagonists; Levodopa; Male; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Rats; Rats, Sprague-Dawley; Rotation; Treatment Outcome

Dextromethorphan has been reported to be a weak antagonist of the ion channel associated with the NMDA receptor, and to have putative antiparkinsonian activity in man. This study looked at the effects of dextromethorphan in normal and monoamine-depleted mice, to determine whether it exhibited a behavioural profile with regard to motor activity that was consistent with NMDA receptor blockade. In normal mice, 5-80 mg/kg i.p. dextromethorphan caused modest muscle relaxation at the highest dose in all animals; hyperlocomotion and stereotypy were evident at 40 mg/kg i.p. in a fraction of mice (4/14). In 24 h reserpine-treated mice, locomotion was reinstated by the dopamine D1 receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine hydrochloride (SKF 38393, 30 mg/kg i.p.), the dopamine D2 receptor agonist N-n-propyl-N-phenylethyl-p-(3-hydroxyphenyl)ethylamine (RU 24213, 5 mg/kg s.c.) and L-3,4-dihydroxyphenylalanine (L-DOPA, 150 mg/kg i.p. in conjunction with benserazide 100 mg/kg i.p.). Dextromethorphan alone (10-40 mg/kg i.p.) caused non-significant arousal of monoamine-depleted mice, but potentiated synergistically movements elicited by SKF 38393 and L-DOPA, though not RU 24213. The possible use of dextromethorphan as an adjunct to L-DOPA in the treatment of Parkinson's disease in man, is discussed.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antiparkinson Agents; Behavior, Animal; Dextromethorphan; Dopamine Agonists; Drug Interactions; Levodopa; Locomotion; Male; Mice; Mice, Inbred Strains; Motor Activity; Parkinson Disease, Secondary; Phenethylamines; Receptors, Dopamine D1; Receptors, Dopamine D2; Reserpine