Intranasal delivery of insulin and a nitric oxide synthase inhibitor in an experimental model of amyotrophic lateral sclerosis Neuroscience Journal Article uri icon
  • Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder in which motor neurons may be targeted by oxidative and nitrergic stress without sufficient compensation by intrinsic support mechanisms. In this work, we addressed two key tenets of this hypothesis for the pathogenesis of ALS. Using superoxide dismutase (SOD) 1(G93A) mice, we studied the impact of reduction of nitrergic stress within the CNS with the use of a broad spectrum nitric oxide synthase (NOS) inhibitor, NG-nitro-l-arginine methyl ester. A separate cohort of SOD1(G93A) mice received direct insulin neurotrophic support, ligating receptors expressed upon motor neurons, to attempt protection against neuronal and functional motor dropout. For direct access, we used a novel form of intranasal delivery that provides peak concentration levels in the CNS within 1 h of delivery without systemic side effects at doses which previously rescued retrograde loss of motor axons after axotomy. To identify even minor impacts of these interventions on the outcome, we utilized an intensive program of serial behavioral and electrophysiological testing weekly, combined with endpoint quantitative morphometry and molecular analysis. This intensive evaluation enhanced our knowledge of the time course in SOD1(G93A) mice and impact of the SOD1(G93A) mutation upon motor neurons and their function. Neither intervention had even minimal impact upon slowing progression of disease in SOD1(G93A) mice. Our data argue against significant roles for nitrergic stress in promoting motor neuron loss and the importance of alternative neurotrophic support mechanisms that might support motor neurons and prevent disease progression in SOD1(G93A) mice.

  • publication date
  • 2008
  • Research
  • Animal Studies
  • Drugs
  • Etiology
  • Intranasal Administration
  • Models
  • Additional Document Info
  • 157
  • issue
  • 4