Neuropeptide Y is a novel bioactive substance that plays a role in the modulation of neurogenesis and neurotransmitter release, and thereby exerts a protective influence against neurodegeneration. Using a sensitive immunohistochemical method with a tyramide signal amplification protocol, we performed a post-mortem analysis to determine the striatal localization profile of neuropeptide Y in neurologically normal individuals and in patients with X-linked dystonia-parkinsonism, a major representative of the neurodegenerative diseases that primarily involve the striatum. All of the patients examined were genetically verified as having X-linked dystonia-parkinsonism. In normal individuals, we found a scattered distribution of neuropeptide Y-positive neurons and numerous nerve fibres labelled for neuropeptide Y in the striatum. Of particular interest was a differential localization of neuropeptide Y immunoreactivity in the striatal compartments, with a heightened density of neuropeptide Y labelling in the matrix compartment relative to the striosomes. In patients with X-linked dystonia-parkinsonism, we found a significant decrease in the number of neuropeptide Y-positive cells accompanied by a marked loss of their nerve fibres in the caudate nucleus and putamen. The patients with X-linked dystonia-parkinsonism also showed a lack of neuropeptide Y labelling in the subventricular zone, where a marked loss of progenitor cells that express proliferating cell nuclear antigen was found. Our results indicate a neostriatal defect of the neuropeptide Y system in patients with X-linked dystonia-parkinsonism, suggesting its possible implication in the mechanism by which a progressive loss of striatal neurons occurs in X-linked dystonia-parkinsonism.

Because of its unique ability to exert long-lasting synaptic transmission blockade, botulinum neurotoxin A (BoNT/A) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability. However, it has been a matter of debate whether this toxin has central or peripheral sites of action. We employed a rat model in which BoNT/A1 or BoNT/A2 was unilaterally injected into the gastrocnemius muscle. On time-course measurements of compound muscle action potential (CMAP) amplitudes after injection of BoNT/A1 or BoNT/A2 at doses ranging from 1.7 to 13.6 U, CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day, and this muscle flaccidity persisted up to the 14th day. Of note, both BoNT/A1 and BoNT/A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose-dependent manner ranging from 1.7 to 13.6 U, and this muscle flaccidity increased until the fourth day and then slowly recovered. Immunohistochemical results revealed that BoNT/A-cleaved synaptosomal-associated protein of 25 kDa (SNAP-25) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT/A1 (10 U) or BoNT/A2 (10 U), although there seemed to be a wider spread of BoNT/A-cleaved SNAP-25 associated with BoNT/A1 than BoNT/A2 in the contralateral spinal cord. This suggests that the catalytically active BoNT/A1 and BoNT/A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord, where they spread through a transcytosis (cell-to-cell trafficking) mechanism. Our results provide evidence for the central effects of intramuscularly administered BoNT/A1 and BoNT/A2 in the spinal cord, and a new insight into the clinical effects of peripheral BoNT/A applications.

To determine the relationship between periodic breathing (PB) during sleep at high altitude and ventilatory chemosensitivities, we studied nine Japanese climbers who participated in the expedition to the Kunlun Mountains (7,167m) in China in 1986. At sea level, ventilatory response to hypoxia (HVR) by isocapnic progressive hypoxia test and to hypercapnia (HCVR) by Read's method were examined. At altitude 5,360 m, respiratory movements of the chest and abdominal wall, Saoz, ECG, and HR were monitored. Seven climbers manifested PB during sleep. There was a significant correlation between PB during sleep and HVR and HCVR (p <0.05). All the climbers showed severe desaturation during sleep. There was a significant negative correlation between degree of desaturation during sleep and HVR (p <0.05). A negative correlation was also detected between PB and the degree of desaturation during sleep. We concluded that ventilatory chemosensitivities play an important role in eliciting PB and that climbers with high HVR can maintain their arterial oxygenation during sleep, due to hyperventilation induced by PB, which is considered an advantageous adaptation for lowland sojourners.

The effects of acetazolamide, a potent carbonic anhydrase inhibitor, and ammonium chloride (NH4C1) on arterial blood gas tension, resting ventilation, and ventilatory responses to CO2 (HCVR) and hypoxia (HVR) were studied in healthy male subjects. Both drugs induced chronic metabolic acidosis with the reduction in plasma bicarbonate by a mean of 7.0 ± 2.0 (S.D.) mM after acetazolamide and by 5.6 ± 1.8 mM after NH4Cl. The ratio in the decrement of Paco2 to that of plasma bicarbonate (d Paco2/d [HC03 ]) was 1.51 in the former and 0.98 in the latter. Both drugs increased inspiratory minute ventilation (Vi) predominantly due to increased tidal volume (VT) with acetazolamide and to increased respiratory frequency (f) with NH4Cl. In HCVR, the increments in C02-ventilation slope and in ventilation at PETco2 60 mmHg after drug administration were 0.77 ± 0.51 l • min -1 • mmHg -1 and 20.0± 11.2 1/mmn with acetazolamide and 0.59 ± 0.40l • min -1 • mmHg -1 and 8.0 ± 2.8 1/mmn with NH4Cl, respectively. On the other hand, HVR both in terms of d Vi/ASao2 slope and of ventilation at Sao2 75% significantly increased after NH4Cl but not after acetazolamide administration. Thus, augmented VT and HCVR in the acetazolamide group and increased f and HVR in the NH4C1 group suggested that the central chemosensitive mechanism in the former and the peripheral chemosensitive mechanism in the latter may predominantly be responsible for the elevated ventilatory activities.