Exendin-4 Reverses Biochemical and Functional Alterations in the Blood-Brain and Blood-CSF Barriers in Diabetic Rats.

Diabetes mellitus (DM) is a metabolic disorder associated with micro- and macrovascular alterations that contribute to the cognitive impairment observed in diabetic patients. Signs of breakdown of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been found in patients and animal models of DM. Breakdown of the BBB and BCSFB can lead to disruptions in cerebral homeostasis and eventually neural dysfunction and degeneration. However, our understanding of the biochemistry underlying barrier protein modifications is incomplete. Herein, we evaluated changes in the levels of specific proteins in the BBB (occludin, claudin-5, ZO-1, and aquaporin-4) and BCSFB (claudin-2 and aquaporin-1) in the hippocampus of diabetic rats, and we also investigated the functional alterations in these barriers. In addition, we evaluated the ability of exendin-4 (EX-4), a glucagon-like peptide-1 agonist that can cross the BBB to reverse the functional and biochemical modifications observed in these animals. We observed a decrease in BBB proteins (except ZO-1) in diabetic rats, whereas the EX-4 treatment recovered the occludin and aquaporin-4 levels. Similarly, we observed a decrease in BCSFB proteins in diabetic rats, whereas EX-4 reversed such changes. EX-4 also reversed alterations in the permeability of the BBB and BCSFB in diabetic rats. Additionally, altered cognitive parameters in diabetic rats were improved by EX-4. These data further our understanding of the alterations in the central nervous system caused by DM, particularly changes in the proteins and permeability of the brain barriers, as well as cognitive dysfunction. Furthermore, these data suggest a role for EX-4 in therapeutic strategies for cognitive dysfunction in DM.

Peripheral Levels of AGEs and Astrocyte Alterations in the Hippocampus of STZ-Diabetic Rats.

Diabetic patients and streptozotocin (STZ)-induced diabetes mellitus (DM) models exhibit signals of brain dysfunction, evidenced by neuronal damage and memory impairment. Astrocytes surrounding capillaries and synapses modulate many brain activities that are connected to neuronal function, such as nutrient flux and glutamatergic neurotransmission. As such, cognitive changes observed in diabetic patients and experimental models could be related to astroglial alterations. Herein, we investigate specific astrocyte changes in the rat hippocampus in a model of DM induced by STZ, particularly looking at glial fibrillary acidic protein (GFAP), S100B protein and glutamate uptake, as well as the content of advanced glycated end products (AGEs) in serum and cerebrospinal fluid (CSF), as a consequence of elevated hyperglycemia and the content of receptor for AGEs in the hippocampus. We found clear peripheral alterations, including hyperglycemia, low levels of proinsulin C-peptide, elevated levels of AGEs in serum and CSF, as well as an increase in RAGE in hippocampal tissue. We found specific astroglial abnormalities in this brain region, such as reduced S100B content, reduced glutamate uptake and increased S100B secretion, which were not accompanied by changes in GFAP. We also observed an increase in the glucose transporter, GLUT-1. All these changes may result from RAGE-induced inflammation; these astroglial alterations together with the reduced content of GluN1, a subunit of the NMDA receptor, in the hippocampus may be associated with the impairment of glutamatergic communication in diabetic rats. These findings contribute to understanding the cognitive deficits in diabetic patients and experimental models.