Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques.

BACKGROUND: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. NEW METHOD: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125I-labeled DNSP-11 dose. RESULTS: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. COMPARISON WITH EXISTING METHODS: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. CONCLUSIONS: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

The abductor pollicis brevis R1 response: normative data and physiological behavior.

BACKGROUND: Although H reflexes cannot be reliably recorded from resting human hand intrinsic muscles, a short latency R1 response, thought to be similar to the H reflex, is readily obtained from upper extremity muscles during voluntary contraction. METHODS: The right and left median nerves of 20 normal subjects were repetitively stimulated at 3 Hz at stimulus intensities corresponding to threshold and 20%, 40% and 60% of maximal M response, recording from the abductor pollicis brevis muscle. Studies were done during both minimal and moderate voluntary contraction. RESULTS: The R1 response was present in all subjects at the 40% stimulation intensity level during moderate contraction. The mean latency was 27 ms (SD 1.77 ms) with a good correlation to arm length. The mean amplitude was 1.17 mV (SD 0.79 mV). CONCLUSIONS: Abductor pollicis muscle R1 response can be reliably measured, although latency showed much less intersubject and side to side variability than amplitude. This technique may be useful for the assessment of demyelinative lesions of the inferior segments of the brachial plexus and C8-T1 roots.