Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

Abstract

Aims/hypothesis Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. Materials and methods The regional pattern of CGU was measured with the 2-deoxy [ 14 C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor β1 (TGFβ1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months.Results Measurement of CGU in 27 brain regions confirmed that TGFβ1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFβ1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFβ1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. Conclusions/interpretation In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.

Intact Memory in TGF-β1 Transgenic Mice Featuring Chronic Cerebrovascular Deficit: Recovery with Pioglitazone

“…Ratios of standard uptake value (SUV) in the activated somatosensory cortex (contralateral to whisker stimulation) relative to the analogous ipsilateral cortex were comparable among all groups. There was a tendency for reduced striatal uptake associated with TGF-b1 overexpression and pio treatment in WT mice, respectively, confirming the basal hypometabolism reported in this model (Galea et al, 2006) and induced by pio (n = 4 to 7 mice per group). Corresponding anatomic levels across groups were selected on the metabolic PET images using average WT and TGF MRI templates as guides.…”

Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain

“…Pioglitazone (20 mg/kg/d, for 16 weeks) only modestly reduced SDS-soluble Aβ levels and did not affect amyloid plaque burden or microglia activation in 11-month old Tg2576 mice, suggesting that PPARγ activation does not greatly affect Aβ levels [163]. Similarly, in a murine model of AD, pioglitazone (120 mg/g/d, for 2 months) decreased cerebral glucose utilization, thus suggesting that it does not act as a metabolic enhancer in AD [164], but rather, it would increase neurotoxicity in the brain, maybe due, at least in part, to a glucose-dependent generation of ROS [39, 165]. Other studies, in contrast, reported major neuroprotective effects following pioglitazone administration, mainly based on reduced glial activation coupled with Aβ reduction-associated cognitive improvement.…”

Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art

“…However, in Phase III placebo-controlled, randomized-clinical trials that were stratified with respect to APOE-genotype, no significant long-term benefit was observed for rosiglitazone monotherapy versus placebo 113, 114 , or when combined with an acetylcholine esterase inhibitor 115 . Small scale studies with pioglitazone, another gamma PPAR agonist drug, have also not produced convincing therapeutic responses 116, 117 .…”