Plasticity of the spinal glymphatic system in male SD rats with painful diabetic neuropathy induced by type 2 diabetes mellitus

Abstract

Painful diabetic neuropathy (PDN) is one of the most common diabetic complications (Iqbal et al., 2018;Schmader, 2002;Schreiber et al., 2015), and is most often described as "burning," "electric," "sharp," and "dull/ache," which, for most, is worse at night time and when tired or stressed (Schmader, 2002). It affects the physical and mental health of patients seriously, leading to sleeping disorders, fatigue, and decreased activity, thus causing substantial interference in the enjoyment of life (Galer et al., 2000;Schmader, 2002).Owing to our limited knowledge of the underlying mechanism of PDN, current treatments are mainly focused on patients' symptoms and the therapeutic effects are unsatisfied (Iqbal et al., 2018;

Aquaporins and Neuropathic Pain

“…Since inflammation, abnormal glutamate metabolism, and abnormal activation of astrocytes are involved in the pathogenesis of PDN, and combined with the regulatory effect of AQP4 on the above metabolic abnormalities, AQP4 may be used as a therapeutic target for PDN. It is worth mentioning that Wang et al [17,59] found that compared with normal rats, the clearance function of the spinal glymphatic system in PDN rats was significantly deceased, and the expression and polarization of AQP4 in lumbar enlargement of the spinal cord were significantly altered.…”

“…Many diseases such as hypothermia, painful diabetic neuropathy, Alzheimer's disease and epilepsy have been manifested to be associated with impaired expression or mislocalization of AQP4 [12,17,[56][57][58]. Interestingly, recent studies have demonstrated the existence of the glymphatic system, which consists of AQP4 and astrocytes and is responsible for removing metabolic waste products from the CNS [17,59] (Fig. 3, Ref.…”

“…In terms of contrast agent selection, the newly discovered contrast agent that can be used to observe the paracellular flow and diffusive transcellular exchange of water is H 2 17 O, which contributes a lot to our better understanding of the glymphatic system [60,61]. Studies have demonstrated that both AQP4 and the glymphatic system are involved in the occurrence and development of many diseases, like Alzheimer's disease, chronic pain, painful diabetic neuropathy, and perioperative neurocognitive disorders [11,12,17,59,62,63]. Since waste removal is essential for the maintenance of normal function in the CNS, which lacks traditional lymphatic vessels, the emergence of the glymphatic system provides new insights into further understanding of neurological diseases [64,65].…”

“…Since waste removal is essential for the maintenance of normal function in the CNS, which lacks traditional lymphatic vessels, the emergence of the glymphatic system provides new insights into further understanding of neurological diseases [64,65]. The glymphatic system with AQP4 as the core is responsible for the excretion of metabolic waste such as glutamate (excitatory neurotransmitter) and water balance in the CNS [17,59]. The inflammation, edema, and neuronal hyperexcitability are also one of the pathogeneses of neuropathic pain [66,67].…”

“…[120][121][122][123]. Moreover, Wang et al [17,59] found that β-hydroxybutyrate could alleviate PDN by restoring the distribution of AQP4 around blood vessels in the spinal glymphatic system based on the abnormal changes of AQP4 in PDN rats. This study further revealed the connection between the AQP4-based glymphatic system and PDN and provided a new therapeutic target for PDN.…”