Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

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Diabetes mellitus (DM), a metabolic disease caused by the deficiency of insulin or the weak response to insulin produced by the body (Xue et al., 2012), is associated with the occurrence of well‐described microvascular complications, including retinopathy, nephropathy, cardiomyopathy, and peripheral neuropathy. Emerging evidence suggests that diabetes may also have negative effects on the central nervous system (CNS), including a series of neurochemical, neurophysiological, and structural abnormalities (Biessels, Staekenborg, Brunner, Brayne, & Scheltens, 2006; Chuiko, Bodykhov, & Skvortsova, 2010), which cumulatively contribute to the prevalence of diabetic encephalopathy (DE). As a critical complication of diabetes (Sima, 2010), with cognitive dysfunction as its core component (Biessels, Deary, & Ryan, 2008), DE has become a point of attraction for researchers in this field. However, the multifactorial pathogenesis of cognitive dysfunction in diabetes presents a mystery that needs to be unraveled (Kodl & Seaquist, 2008).
While neurotransmitters are biologically active molecules that play fundamental roles in maintaining brain physiological function, their metabolic alterations have been reported to be closely related to many neurodegenerative diseases such as Alzheimer disease (AD) (Fedotova et al., 2016), Huntington disease (HD) (Garcia‐Miralles et al., 2016), Parkinson disease (PD) (Politis et al., 2014), and of course DE (Zhou et al., 2015). There is growing evidence that explains the implication of the neurotransmitter system in the early pathophysiology of cognitive impairment (Prakash, Kalra, Mani, Ramasamy, & Majeed, 2015; Zhou et al., 2015), and degenerative encephalopathy has also been diagnosed by several neurotransmitter systems (Levenga et al., 2013). Moreover, monoamine neurotransmitters, especially tryptophan (Trp) and its metabolites, have recently been spotted for their important regulatory effect on attention, memory, and reaction ability (Vermeiren, Van Dam, Aerts, Engelborghs, & De Deyn, 2014).
Trp metabolic routes, including the branches of the serotonin (5‐HT) and kynurenine pathway (KP), are shown in Figure 1a. During the development and maturation of synapses, 5‐HT promotes their formation and maintenance in the cerebral cortex. This Trp derivative was confirmed to be reduced in all regions of the amygdala, caudate, putamen, and temporal cortex of AD patients, while its downstream metabolite, as well as 5‐hydroxyindoleacetic acid (5‐HIAA), were depleted in the amygdala and caudate (Nazarali & Reynolds, 1992). On the contrary, another major degradation pathway of Trp is KP. Kynurenine is the precursor of various metabolites with quite varied biological functions. It can be catabolized through three specific pathways to generate anthranilic acid, 3‐hydroxykynurenine (3‐HK), and kynurenic acid (KYNA) by the enzymes kynureninase, kynurenine 3‐monooxygenase, and kynurenine aminotransferase, respectively (Schwarcz & Stone, 2017). Along the KMO branch, kynurenine is converted to 3‐HK, which is further degraded to 3‐hydroxyanthranilic acid (3‐HAA). 3‐HAA is further metabolized into aminocarboxymuconic semialdehyde, an unstable intermediate that is nonenzymatically transformed into quinolinic acid (QUIN). Guidetti and Schwarcz (2003) have suggested that the generation of toxic free radicals is responsible for the substantial potentiation of excitotoxicity, when neurons are concomitantly exposed to both 3‐HK and QUIN. Animal studies have also demonstrated that peripheral kynurenine and 3‐HK are actively transported from the circulation through the blood‐brain barrier (Fukui, Schwarcz, Rapoport, Takada, & Smith, 1991). Increased serum 3‐HK levels therefore lead to an increased brain content of 3‐HK. Furthermore, patients with AD were observed to have significantly increased 3‐HK levels in serum compared with patients with major depression and individuals with subjective cognitive impairment (Schwarz, Guillemin, Teipel, Buerger, & Hampel, 2013). Thus, the decrease of 5‐HT and the accumulation of the metabolites of KP in CNS may suggest the occurrence of cognitive dysfunction.
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