Low pH of interstitial fluid around hippocampus of the brain in diabetic OLETF rats

Abstract

Background: We have reported that pH values of ascites and interstitial fluids around the liver in Otsuka Long-Evans Tokushima Fatty (OLETF) rats are significantly lower than normal pH, 7.40, of mammalian body fluids (Biochem Biophys Res Commun 2013, 432:650), and that this lowered pH of interstitial fluid causes the insulin resistance in diabetic patients by decreasing insulin-binding to its receptors (J Physiol Sci 2013, 63:S199). In the preset study, we tried to measure the interstitial fluid pH in diabetic OLETF rats, since the interstitial fluid pH plays key factors in the brain function from a viewpoint of the binding affinity of neurotransmitters to their receptors.

Findings: We found that the pH value of interstitial fluids around hippocampus, the most important area for memory, in diabetic OLETF rats was lower than that in normal rats by measuring pH with antimony pH electrodes.

Conclusions: The lowered pH of interstitial fluid around hippocampus of the brain in diabetic rats observed in the present study suggests that the function of hippocampus of the brain would be diminished due to low affinity of various types of neurotransmitters, playing key roles in the hippocampus function, to their receptors. Therefore, we indicate that maintenance of the interstitial fluid pH at the normal level would be one of the most important key factors for molecular and cellular therapies in various types of diseases including diabetes mellitus.

Keywords: Antimony pH electrode; Diabetes mellitus; Hippocampus; OLETF rat; pH.

Figure 1

pH of interstitial (extracellular) fluid around hippocampus of OLETF and normal (Wistar) ratsv. The pH value is shown as the mean, and the error bar indicates SEM. The pH values shown in Figure 1 were measured at 60 and 90 min after antimony pH electrodes reached interstitial (extracellular) fluids around hippocampus of the OLETF rats (closed columns) and normal (Wistar) rats (open columns). n = 4. *, p < 0.05 compared with that in normal (Wistar) rats at each measured time.

Figure 2

The potential molecular mechanism of pH-dependent regulation of neural cell function in diabetes mellitus with mitochondria dysfunction. Neural cells with mitochondria dysfunction synthesize ATP required for maintenance of neural cell function only or mainly via glycolysis, producing much larger amounts of H⁺ than neural cells with normal function of mitochondria synthesizing ATP via TCA cycle. This large amount of H⁺ produced by glycolysis in neural cells with dysfunction of mitochondria is released to the extracellular space (interstitial fluid) including the synaptic cleft. This phenomenon results in lowered pH of the extracellular space (interstitial fluid) including the synaptic cleft. Activity of neural cells at lowered pH of the extracellular space (interstitial fluid) is kept low due to a low level of synaptic neurotransmission signals via low binding affinity of neurotransmitters to their receptors. Namely, the amount of neurotransmitters released into the synaptic cleft, which is large enough for generation of action potential under conditions with normal function of mitochondria, is insufficient for generating action potential under lowered pH conditions due to low binding affinity of neurotransmitters to their receptors.