Antinociceptive effect of VD-Hemopressin in a model of central neuropathic pain associated with streptozotocin neurodegeneration

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory with impaired cognitive functions. The two subtypes are familial AD, influenced by a genetic mutation with subsequent metabolism / abnormal extracellular deposition of the beta amyloid peptide (bA) and collapse of the cytoskeleton by hyperphosphorylation of the tau protein in the hippocampus; and sporadic AD, which has recently been described as resulting from a deficiency in cerebral glucose metabolism. Pain is a common problem in people who suffer from dementia. In AD, it manifests as central neuropathic pain (CP), caused by injury to the central nervous system that leads the patient to develop hypersensitivity symptoms that manifest themselves in the form of hyperalgesia and allodynia, being seen as a comorbidity that ends up being treated with much neglect due to the patient's communication difficulties. In this context, glial activation and neuroinflammation are not only characteristic features of CP, they are common events both in AD and in cases of impaired hippocampal functions in cases of neuropathic pain. The peptides of the hemopressin (Hp) family are a tool with great potential for the treatment of neuropathic pain and AD, given its ability to modulate the activity of the endocannabinoid system via specific receptors. Recent results demonstrate that type 1 cannabinoid receptor (CB1R) agonism reverses astrogliosis-associated neuroinflammation in the presence of bA, negatively regulating the expression of the nuclear factor Kappa B, interleukin 1 beta (IL-1b) and the alpha tumor necrosis (TNF-a). And although VD-Hp (an extended form of Hp and CB1R agonist) has been shown to have an antinociceptive effect, little is known about its effect on the inflammatory response associated with AD in the hippocampus. Therefore, it is necessary to investigate its possible effects on neuroinflammation in a model of CD associated with neurodegeneration, induced by streptozotocin (STZ). Therefore, male Wistar rats (90 days, 250-350 kg) will be submitted to a bilateral intracerebroventricular (icv) injection of STZ in order to mimic the neurodegeneration characteristic of sporadic Alzheimer's disease. VD-Hp (0.25 mg / kg) will be administered (intraperitoneally) for 7 consecutive days (once a day), with the mechanical sensitivity of the animals being assessed by von Frey monofilaments on the 3rd, 7th, 12th and 15th days, as well such as cognitive assessment through the object recognition test on the 5th and 6th days. At the end of the experimental period, samples of the hippocampus will be collected for analysis of immunofluorescence, protein and gene expression related to aspects of neuroinflammation. The results obtained in this project will be fundamental so that, through new therapeutic methods, a better quality of life is provided for patients affected by AD who suffer from neuropathic pain.