Long-term abnormalities in brain glucose/energy metabolism after inhibition of the neuronal insulin receptor: implication of tau-protein

Abstract

SummaryThe triplicate intracerebroventricular (icv) application of the diabetogenic compound streptozotocin (STZ) in low dosage was used in 1-year-old male Wistar rats to induce a damage of the neuronal insulin signal transduction (IST) system and to investigate the activities of hexokinase (HK), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GDH), pyruvate kinase (PK), lactate dehydrogenase (LDH) and a-ketoglutarate dehydrogenase (a-KGDH) in frontoparietotemporal brain cortex (ct) and hippocampus (h) 9 weeks after damage. In parallel, the concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine triphosphate (GTP) and creatine phosphate (CrP) were determined. We found reductions of HK to 53% (ct) and 60% (h) of control, PFK to 63=64% (ct=h); GDH to 56=61% (ct=h), PFK to 57=59% (ct=h), a-KGDH to 37=35% (ct=h) and an increase of LDH to 300=240% (ct=h). ATP decreased to 82=87% (ct=h) of control, GTP to 69=81% (ct=h), CrP to 82=81% (ct=h), $P to 82=82% (ct=h), whereas ADP increased to 189=154% (ct=h). The fall of the activities of the glycolytic enzymes HK, PFK, GDH and PK was found to be more marked after 9 weeks of damage when compared with 3-and 6-week damage whereas the diminution in the concentration of energy rich compound was stably reduced by between 20 and 10% relative to control. The abnormalities in glucose=energy metabolism were discussed in relation to tau-protein mismetabolism of experimental animals, and of sporadic AD.

Neuroprotective Effect of Cyclooxygenase Inhibitors in ICV-STZ Induced Sporadic Alzheimer’s Disease in Rats

“…It has been reported that there is an increase in LDH activity after ICV-STZ administration in brain of rats (Hoyer and Lannert 2007). Consistent to this, in the present study, ICV-STZ-treated animals showed a marked increase in LDH which was prevented by pretreatment with COX-1 and/or COX-2, but not COX-3, inhibitor.…”

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

“…The intracerebroventricular (icv) administration of the diabetes-inducing drug streptozotocin (icv-STZ) has been investigated as a non-transgenic model of sAD (Lester-Coll et al, 2006;Salkovic-Petrisic and Hoyer, 2007). Subdiabetogenic doses of icv-STZ (1-3 mg/kg) mimic features of human sAD, such as metabolic dysfunctions (Hoyer and Lannert, 2007), brain insulin resistance associated with tau protein hyperphosphorylation (Gru¨nblatt et al, 2007;Barilar et al, 2015), Ab-like aggregation in meningeal vessels (Salkovic-Petrisic et al, 2011), cholinergic deficits (Blokland and Jolles, 1993), and memory impairments (Lannert and Hoyer, 1998;Agrawal et al, 2011). Taking into consideration that STZ does not cross the blood-brain barrier, icv-STZ decrease cerebral glucose uptake without altering blood glucose level (Grieb, 2016).…”

Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

“…Multiple parenteral treatments with low-to-moderate STZ doses cause insulin resistance and type 2 diabetes mellitus by affecting insulin receptor (IR) signalling (Blondel and Portha 1989;Giorgino et al 1992;Kadowaki et al 1984). Icv administration of low STZ doses does not induce a systemic diabetic condition in rats, but has been convincingly shown to induce insulin-resistant brain state characterized by altered tyrosine kinase activity of IR and dysfunctional signalling downstream the IR signaling pathways (Agrawal et al 2010(Agrawal et al , 2011Grünblatt et al 2007;Lester-Coll et al 2006;Osmanovic-Barilar et al 2014;Salkovic-Petrisic et al 2006;Steen et al 2005), accompanied by a decrease in brain glucose and energy metabolism (Hoyer and Lannert 2007;Lannert and Hoyer 1998;Nitsch and Hoyer 1991;Plaschke and Hoyer 1993). Additionally, the STZ-icv rat model has been demonstrated to develop remarkable behavioral and neuropathological AD-like features, in particular cognitive (Mayer et al 1990) and brain cholinergic deficits (Hellweg et al 1992), as well as oxidative stress (Correia et al 2013;Sharma and Gupta 2001), neuroinflammation, and astrogliosis (Chen et al 2013;Javed et al 2011;Kraska et al 2012;Prickaerts et al 1999Prickaerts et al , 2000Rodrigues et al 2010;Shoham et al 2003Shoham et al , 2007.…”