Differential Effects of Hypoglycemia and Excitotoxic Signals on SN56 Septal Cholinergic Neuronal Cells

Glucose is a principal energy substrate for the brain. Hypo- and hyperglycemic episodes are frequent in senescent people thereby contributing to functional and structural impairment of brain neurons, yielding cognitive deficits in this population. In this report we investigate whether long-term changes in extracellular concentration of glucose may affect viability and transmitter functions of septum-originated SN56 cholinergic neuronal cells through alterations in their acetyl-CoA availability. Cell phenotypes with low (NC) and cAMP/retinoic acid in-duced, high expression cholinergic phenotype (DC) were investigated. Hypoglycemia brought about similar about 20-30% decreases of in pyruvate dehydrogenase complex (PDHC) and ATP-citrate lyase (ACLY) and 65% decline of lactate dehydrogenase (LDH) activities in NC and DC, respectively. Choline acetyltransferase (ChAT) and LDH activities in DC were about 3 to 8 and 1.7 to 2.4 times higher than in NC, over the entire range of glucose concen-trations, respectively. In effect DC appeared to be more resistant than NC to hypoglycemia, as evidenced by lower values of [IC50] of glucose against cell count and intracellular LDH, re-spectively. On the other hand, some of functional properties of DC such as cholinergic phe-notype (ChAT) and plasma membrane function (trypan blue exclusion, TB+) were found to be more prone to hypoglycemia than in NC, as demonstrated by higher respective [IC50] for glu-cose in DC. Acetyl-CoA levels in DC were 40% lower than those in NC, and both decreased parallelly with deepening hypoglycemia by about 25%. Cytotoxic effects of amyloid-β25-35 (Aβ) and sodium nitroprusside (NO generator-SNP) in those conditions were tested. In 25 mM glucose medium these toxic compounds in DC exerted greater detrimental effects than in NC. On the contrary, in 1 mM glucose more evident cytotoxicity of SNP and Aβ was ob-served in NC. These data may indicate that higher rate of glycolysis in differentiated cholin-ergic septal neurons may establish a protective mechanism against hypoglycemia.