Elsevier

Neuroscience

Volume 170, Issue 1, 29 September 2010, Pages 298-307
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Quinolinate induces selective loss of melanin-concentrating hormone neurons, rather than orexin neurons, in the hypothalamus of mice and young rats

https://doi.org/10.1016/j.neuroscience.2010.06.081Get rights and content

Abstract

Orexins are neuropeptides produced in the lateral hypothalamus and implicated in regulation of sleep-wake cycle. Selective loss of orexin neurons is found in the brain of patients with narcolepsy, but the mechanisms of this pathological change are unclear. A previous study showed that excessive stimulation of N-methyl-d-aspartate (NMDA) receptors by quinolinic acid (QA) caused selective loss of orexin neurons in rat hypothalamic slice culture. Here we examined QA toxicity on orexin neurons and melanin-concentrating hormone (MCH) neurons in vivo. Contrary to the expectation, injection of QA (60 and 120 nmol) into the lateral hypothalamus of male C57BL/6 mice caused selective loss of MCH neurons rather than orexin neurons, and this toxicity of QA was attenuated by MK-801, an NMDA receptor antagonist. Selective loss of MCH neurons with preserved orexin neurons was observed even when GABAA receptor antagonists such as bicuculline and picrotoxin were injected with QA. A significant decrease in the number of orexin neurons was induced when QA injection was performed in the dark phase of diurnal cycle, but the degree of the decrease was still lower than that in the number of MCH neurons. Finally, QA (60 nmol) induced selective loss of MCH neurons also in young rats at 3–4 weeks of age. These results do not support the hypothesis that acute excitotoxicity mediated by NMDA receptors is responsible for the pathogenesis of narcolepsy.

Section snippets

Drugs

QA and (+)-MK-801 maleate were obtained from Wako Chemicals (Osaka, Japan). Picrotoxin, (−)-bicuculline methiodide and muscimol hydrobromide were obtained from Sigma-Aldrich Chemicals (St. Louis, MO, USA). QA free acid was dissolved at 400 mM in equimolar NaOH and diluted in phosphate-buffered saline (PBS) to give final concentrations. MK-801, picrotoxin, bicuculline and muscimol (the final concentration was 20, 4, 2 and 0.6 mM, respectively) were dissolved in PBS and mixed with QA solution at

QA causes preferential loss of MCH neurons via NMDA receptor activation in adult mice

QA is an endogenous excitotoxin implicated in pathogenesis of several neurological disorders associated with neurodegeneration. Notably, application of this compound to hypothalamic slice cultures substantially decreased the number of viable orexin neurons while showing little effect on the number of MCH neurons (Katsuki and Akaike, 2004). Therefore, we performed unilateral microinjection of QA into the lateral hypothalamus of adult mice, to clarify if QA produced selective cytotoxicity on

Discussion

In the brain of narcolepsy patients, orexin neurons in the hypothalamus are substantially decreased, whereas MCH neurons in the same area are preserved (Peyron et al., 2000, Thannickal et al., 2000). The mechanisms of selective loss of orexin neurons remain unsolved. Indeed, very few studies addressed this issue directly. Gerashchenko and Shiromani (2004) reported that chronic infusion of lipopolysaccharide into the lateral hypothalamus of adult rats resulted in a significant decrease in the

Conclusion

In conclusion, the present study proposes that acute excitotoxic injury may not be primarily responsible for the pathogenesis of narcolepsy. The clearly different results in whole animals from those in organotypic slice cultures casts a caution, with respect to neurodegenerative processes of hypothalamic orexin neurons, to extrapolate in vitro findings to in vivo situations.

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research from The Japan Society for the Promotion of Science and The Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Dr. Fumio Soeda and Dr. Kazuo Takahama (Kumamoto Univ.) for assistance in behavioral experiments.

References (39)

  • S. Nishino et al.

    Hypocretin (orexin) deficiency in human narcolepsy

    Lancet

    (2000)
  • S. Overeem et al.

    Narcolepsy: immunological aspects

    Sleep Med Rev

    (2008)
  • C. Peyron et al.

    Role of the melanin-concentrating hormone neuropeptide in sleep regulation

    Peptides

    (2009)
  • T. Sakurai et al.

    Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice

    Neuron

    (2005)
  • T.W. Stone

    Kynurenines in the CNS: from endogenous obscurity to therapeutic importance

    Prog Neurobiol

    (2001)
  • T.C. Thannickal et al.

    Reduced number of hypocretin neurons in human narcolepsy

    Neuron

    (2000)
  • J.T. Willie et al.

    Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression

    Neuroscience

    (2008)
  • S. Yamazaki et al.

    Intracerebroventricular injection of the antibiotic cefoselis produces convulsion in mice via inhibition of GABA receptors

    Pharmacol Biochem Behav

    (2002)
  • M. Abercrombie

    Estimation of nuclear population from microtome sections

    Anat Rec

    (1946)

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