Apoptosis of vasopressinergic hypothalamic neurons in chronic diabetes mellitus.
The hyperosmolality associated with diabetes mellitus triggers an increase in neuronal activity and vasopressin production within magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus (SON). In this study, we examined the effect of chronic diabetes on the function and survival of these neurons. After 6 months, but not 6 weeks, of streptozotocin (STZ)-induced diabetes, we observed an increase in the appearance of small hyperchromatic neurons and a decrease in SON neuronal density. A subpopulation of neurons within the SON at this time point demonstrated positive staining for cleaved caspase-3 and TUNEL, two markers of apoptosis. In addition, the number of vasopressin-positive neurons was decreased. Markers for apoptosis did not colocalize with vasopressin immunopositivity; this was probably due to a diabetes-induced degenerative process causing downregulation of vasopressin expression or depletion of neuropeptide. Although the phenotypes of the apoptotic neurons were not identified, other SON neurons including oxytocin-producing neurons are unlikely to be affected by chronic hyperglycemia. Microglial hypertrophy and condensation were also observed in the 6-month diabetic SON. Although upregulation of vasopressin production in response to acute hyperosmolality is adaptive, prolonged overstimulation of vasopressin-producing neurons in chronic diabetes results in neurodegeneration and apoptosis.
Department of Neurology and PVA/EPVA Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
Joshua P
JP
Klein
Bryan C
BC
Hains
Matthew J
MJ
Craner
Joel A
JA
Black
Stephen G
SG
Waxman
D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D017209:Apoptosis / Q000502:physiology*; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013495:Supraoptic Nucleus / Q000378:metabolism / Q000473:pathology*; D014667:Vasopressins / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000502:physiology
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D014667:Vasopressins; D051926:Basigin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases