Johns Hopkins Drug Discovery - Project - Chemotherapy-Induced Neropathy
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HIV-Associated Neurocognitive Disorders (HAND)

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As key members of the Johns Hopkins NIMH Center for Novel Therapeutics for HIV-Associated Neurocognitive Disorders (HAND), JHDD scientists are contributing to the discovery of potential new treatments for HAND. HAND encompasses a hierarchy of progressive neurocognitive impairments up to and including cognitive, motor and behavioral abnormalities, 1-3 and remains a central health issue in patients with chronic HIV infection on combination antiretroviral therapy (cART). 4, 5 In a recent study examining HIV-infected adults recruited from six university clinics across the United States, nearly half of HIV-infected individuals without confounding conditions had some form of HAND. 6

Multiple, novel drug targets with therapeutic promise for HAND are under investigation in JHDD and collaborating labs. Administration of intranasal insulin represents one of these approaches, based on several preclinical and clinical reports indicating a role for this hormone in cognitive function 7-14 and HAND pathology15-18. A recent study found intranasal insulin to improve cognition in a feline model of HAND.15 Because peripheral administration of insulin can cause hyperinsulinemia and hypoglycemia, insulin therapy utilization for cognition enhancement has focused on intranasal administration. Intranasal administration can provide rapid delivery of insulin selectively to the brain via bulk flow along olfactory and trigeminal perivascular channels, and via olfactory bulb axonal transport while maintaining peripheral euglycemia [64-66]. This advantage of intranasal dosing has been replicated in preclinical testing of compounds developed by JHDD which show improved brain exposure when administered via the intranasal route in rodents and non-human primates.20

 

Studies are now ongoing to test the effect of intranasal insulin on cognition in a rodent model of HAND, and to fully characterize the pharmacokinetics of insulin administered via this route. Efforts to delineate the mechanism of insulin efficacy in HAND are also underway with particular attention being paid to the effect of insulin on energy metabolism in key brain regions, as well as a potential effect on viral load. These experiments will inform study design and dose selection for a clinical trial of intranasal insulin administration in HAND patients currently being enrolled by Johns Hopkins collaborators.

References

  1. McArthur, J. C.; Steiner, J.; Sacktor, N.; Nath, A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann. Neurol. 2010, 67, 699-714.
  2. Antinori, A.; Arendt, G.; Becker, J. T.; Brew, B. J.; Byrd, D. A.; Cherner, M.; Clifford, D. B.; Cinque, P.; Epstein, L. G.; Goodkin, K.; Gisslen, M.; Grant, I.; Heaton, R. K.; Joseph, J.; Marder, K.; Marra, C. M.; McArthur, J. C.; Nunn, M.; Price, R. W.; Pulliam, L.; Robertson, K. R.; Sacktor, N.; Valcour, V.; Wojna, V. E. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007, 69, 1789-1799.
  3. Kaul, M.; Zheng, J.; Okamoto, S.; Gendelman, H. E.; Lipton, S. A. HIV-1 infection and AIDS: consequences for the central nervous system. Cell Death Differ. 2005, 12 Suppl 1, 878-892.
  4. Zink, M. C. Translational research models and novel adjunctive therapies for neuroAIDS. J Neuroimmune Pharmacol 2007, 2, 14-9.
  5. Saylor, D.; Dickens, A. M.; Sacktor, N.; Haughey, N.; Slusher, B.; Pletnikov, M.; Mankowski, J. L.; Brown, A.; Volsky, D. J.; McArthur, J. C. HIV-associated neurocognitive disorder – pathogenesis and prospects for treatment. Nature reviews. Neurology 2016, 12, 309.
  6. Heaton, R. K.; Clifford, D. B.; Franklin, D. R., Jr.; Woods, S. P.; Ake, C.; Vaida, F.; Ellis, R. J.; Letendre, S. L.; Marcotte, T. D.; Atkinson, J. H.; Rivera-Mindt, M.; Vigil, O. R.; Taylor, M. J.; Collier, A. C.; Marra, C. M.; Gelman, B. B.; McArthur, J. C.; Morgello, S.; Simpson, D. M.; McCutchan, J. A.; Abramson, I.; Gamst, A.; Fennema-Notestine, C.; Jernigan, T. L.; Wong, J.; Grant, I. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2008, 75, 2087-96.
  7. Craft, S.; Asthana, S.; Newcomer, J. W.; Wilkinson, C. W.; Matos, I. T.; Baker, L. D.; Cherrier, M.; Lofgreen, C.; Latendresse, S.; Petrova, A.; Plymate, S.; Raskind, M.; Grimwood, K.; Veith, R. C. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 1999, 56, 1135-40.
  8. Hoyer, S. The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm 2002, 109, 341-60.
  9. Gasparini, L.; Netzer, W. J.; Greengard, P.; Xu, H. Does insulin dysfunction play a role in Alzheimer’s disease? Trends Pharmacol Sci 2002, 23, 288-93.
  10. Kern, W.; Born, J.; Schreiber, H.; Fehm, H. L. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes 1999, 48, 557-63.
  11. Park, C. R.; Seeley, R. J.; Craft, S.; Woods, S. C. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000, 68, 509-14.
  12. Park, C. R. Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 2001, 25, 311-23.
  13. Zhao, W. Q.; Alkon, D. L. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 2001, 177, 125-34.
  14. Craft, S.; Peskind, E.; Schwartz, M. W.; Schellenberg, G. D.; Raskind, M.; Porte, D., Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998, 50, 164-8.
  15. Mamik, M. K.; Asahchop, E. L.; Chan, W. F.; Zhu, Y.; Branton, W. G.; McKenzie, B. A.; Cohen, E. A.; Power, C. Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 2016, 36, 10683-10695.
  16. Grinspoon, S. K.; Bilezikian, J. P. HIV disease and the endocrine system. N Engl J Med 1992, 327, 1360-5.
  17. Sellmeyer, D. E.; Grunfeld, C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 1996, 17, 518-32.
  18. Grinspoon, S.; Corcoran, C.; Stanley, T.; Katznelson, L.; Klibanski, A. Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 1998, 83, 4251-6.
  19. Dhuria, S. V.; Hanson, L. R.; Frey, W. H., 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. Journal of pharmaceutical sciences 2010, 99, 1654-73.
  20. Rais, R.; Wozniak, K.; Wu, Y.; Niwa, M.; Stathis, M.; Alt, J.; Giroux, M.; Sawa, A.; Rojas, C.; Slusher, B. S. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration. PloS one 2015, 10, e0131861.
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