Investigation of Natural Compounds for Therapeutic Potential in Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain

Abstract

Diabetic neuropathy (DN) is a serious microvascular complication of diabetes mellitus (DM) that impacts the nervous system. Several risk factors are involved in the progression and maintenance of DN-associated pain, such as higher expression of various inflammatory mediators, e.g., tumor necrotic factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), and cyclo-oxygenase-2 (COX-2). The present research explores the neuroprotective potential of natural isolates, including berbamine, bergapten, and carveol, on the DM-induced neuroinflammation and neurodegeneration that cause neuropathic pain. The study utilized computerized techniques, including computational analysis (a docking assay and a molecular dynamic simulation) before moving to in vivo protocols. Diabetic neuropathy was induced by intraperitonial injection (IP) of streptozotocin (65 mg/kg), and the animal subjects (rats) were kept for 4 weeks for the development of DN. Once diabetic neuropathy was confirmed, the subjects were treated with berbamine, bergapten, and carveol until the sixth week (i.e., 2 weeks of treatment). At the sixth week, the rats were sacrificed, and the sciatic nerve and spinal cord of each was collected for further molecular investigation. Docking and a molecular dynamic simulation (MDS) delivered the information that the natural compounds (berbamine, bergapten, and carveol) were interacting with the selected target protein (i.e., mitogen-activated protein kinase). After IP, it was found that berbamine, bergapten, and carveol had ameliorated mechanical allodynia and thermal hyperalgesia by the 28th day of the study (2 weeks after treatment) without affecting blood glucose levels. Berbamine, bergapten, and carveol markedly elevated the levels of glutathione (GSH) and glutathione s-transferase (GST), in both the sciatic nerve and spinal cord, and also reduced lipid peroxidase (LPO) and nitric oxide (NO). The abovementioned natural isolates reduced pathologic alterations provoked through DN, a finding confirmed through histopathological assays (hematoxylin and eosin staining and immuno-histochemical analysis). Treatment down regulated higher expressions of the inflammatory mediatorcyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and nuclear factor kappa B (NF-κB), as confirmed by ELISA and polymerase chain reaction (PCR). The outcomes of berbamine, bergapten, and carveol are compared with those of pregabalin as a positive control group. Compared to pregabalin, treatment with the aforementioned three natural compounds improved nociception and reduced hyperalgesic effects, and consequently reduced pain perception and inflammation. Our results suggest the mechanism for the neuro-protective impact of berbamine, bergapten, and carveol might possibly be arbitrated via COX-2, TNF-α, and NF-κB, and regulated by mitogen-activated protein kinase, ultimately ameliorating STZ-provoked, DM-induced neuroinflammation and neurodegeneration, and associated neuropathic pain.

Association between oxidative stress and chronic orofacial pain and potential druggable targets: Evidence from a Mendelian randomization study

“…For example, the natural compounds in Paclitaxel increased the protective GST levels in the sciatic nerve and spinal cord, 47 as well as the therapeutic effects of Atorvastatin 15 and Streptozotocin. 48 The fact that our findings also suggested that GST was associated with an increased incidence of dentoalveolar pain, while additional epidemiological research and more focused laboratory investigations are required to understand the biochemical and chemical biological underpinnings for these correlations. process and regulating the nitrogen metabolism pathway.…”

Neuroprotective Potential of Hygrophila auriculata Targeting Oxidative Stress-Mediated Deficits in Streptozotocin-Induced Sciatic Nerve Injury

“…30 STZ causes hyperglycemia and thereby altering the nociceptive response. 31,32 In this study, rats that were sensitized to STZ had significantly higher levels of serum glucose and glycohemoglobin (HbA1c), lower body weight, and higher amounts of food, water, and urine intake than ND rats. Along with mechanotactile allodynia, diabetic animals also show signs of mechanical and thermal hyperalgesia in the Randall-Selitto, von Frey hair, Eddy's hot plate, and tail-flick tests.…”

Pharmacological investigation of taxifolin for its therapeutic potential in depression

“…A previously published method was used to determination of GST levels, with slight modifications [ 36 ]. 1-chloro-2,4-dinitrobenzol (CDNB) was utilized as a substrate to measure GST activity in homogenized tissue samples.…”