Characterization of striatum-mediated behavior and neurochemistry in the DJ-1 knock-out rat model of Parkinson's disease.

The recently developed DJ-1 knockout (KO) rat models the DJ-1 (or PARK7) loss-of-function mutation responsible for one form of early-onset familial Parkinson's disease (PD). Prior studies demonstrate that DJ-1 KO rats present progressive dopamine (DA) cell body degeneration in the substantia nigra pars compacta between 4 and 8 months of age. Furthermore, as some motor deficits emerge before the significant loss of DA cells, this mutation may yield a period of DA neuron dysfunction preceding cell death that may also contribute to cognitive impairments in early PD. However, cognitive functions subserved by corticostriatal circuitry, as well as additional alterations to the neurochemistry of monoamine systems, are largely uncharacterized in the DJ-1 KO rat. We therefore assessed a variety of striatally-mediated behavioral tasks, as well as the integrity of dopamine and serotonin systems, in male DJ-1 KO rats and wild-type (WT) controls at 4, 6, and 8 months of age. We demonstrate that DJ-1 KO rats exhibited motor impairments, but have intact goal-directed control over behavior in an appetitive instrumental learning task. Further, preprotachykinin mRNA expression, a post-synaptic indicator of DA signaling, was significantly decreased in 4-month DJ-1 KO rats, while DA transporter binding in the dorsal striatum did not differ between genotypes at any of the ages examined. Striatal tyrosine hydroxylase levels were significantly increased in 8-month DJ-1 KO rats and tended to be higher than WT at 4 and 6 months. Lastly, serotonin transporter binding was increased in the medial and orbitofrontal cortices of 4-month old DJ-1 KO rats. These results suggest that the nigrostriatal dopaminergic and prefrontal serotoninergic systems are altered early in the progression of DJ-1 KO pathology, despite no overt loss of the DA innervation of the striatum, and thus may be associated with early alterations in the functions of corticostriatal systems.

Menadione (vitamin K3) inhibits hydrogen sulfide and substance P via NF-кB pathway in caerulein-induced acute pancreatitis and associated lung injury in mice.

OBJECTIVE: We aim to study the protective effect of menadione on caerulein-induced acute pancreatitis (AP) and associated lung injury and to explore the possible mechanism. METHODS: Male Swiss mice randomized into control and different experimental groups. AP was induced in mice by six hourly intraperitoneal (i.p) injections of caerulein (50 µg/kg at 1 h interval). Menadione (10 mg/kg) was administered one hour (i.p, 10 mg/kg) after the first caerulein injection and control animals were given hourly intraperitoneal (i.p) injection of isotonic sodium chloride solution for 6 hours. RESULTS: Administration of menadione attenuated the severity of AP and associated lung injury as shown by the histopathology, reduced MPO and serum amylase activity. Further, the anti-inflammatory effect of menadione was associated with a reduction of pancreatic and pulmonary proinflammatory cytokine interleukin 1ß (IL-1ß) and hydrogen sulfide (H2S). Moreover, menadione inhibited caerulein-induced cystathionine-γ-lyase, preprotachykinin-A (PPTA) and neurokinin-1 receptor (NK-1R) expression in pancreas and lungs. Also menadione further enhances the beneficial effect by reducing caerulein-induced nuclear factor (NF) -κB activation in both pancreas and lung. CONCLUSION: The present findings show for the first time that in AP, menadione may exhibit an anti-inflammatory effect by down-regulating substance-P and H2S signaling via the NF-кB pathway.

Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats.

BACKGROUND AND PURPOSE: Although substance P (SP) and neurokinin NK1 receptors have been reported to be involved in cisplatin-induced acute and delayed emesis, their precise roles remain unclear. Pica, the consumption of non-nutrient materials such as kaolin in rats, can be used as a model of nausea in humans. We investigated the time-dependent changes in cisplatin-induced pica and the involvement of SP and NK1 receptors in this behaviour. EXPERIMENTAL APPROACH: Rats were administered cisplatin with or without a daily injection of a 5-HT3 receptor antagonist (granisetron) or an NK1 receptor antagonist (aprepitant), and kaolin intake was then monitored for 5 days. The effects of granisetron on the cisplatin-induced expression of preprotachykinin-A (PPT-A) mRNA, which encodes mainly for SP, and on SP release in the medulla, measured by in vivo brain microdialysis, were also investigated. KEY RESULTS: Cisplatin induced pica within 8 h of its administration that continued for 5 days. Granisetron inhibited the acute phase (day 1), but not the delayed phase (days 2-5), of pica, whereas aprepitant abolished both phases. Within 24 h of the injection of cisplatin, PPT-A mRNA expression and SP release in the medulla were significantly increased; these findings lasted during the observation period and were inhibited by granisetron for up to 24 h. CONCLUSIONS AND IMPLICATIONS: The profiles of cisplatin-induced pica in rats are similar to clinical findings for cisplatin-induced emesis in humans, and we showed that SP production in the medulla and activation of NK1 receptors are involved in this cisplatin-induced pica.