How does the nervous system relate to internal temperature? Even though it is an old theory, it's believed that receptor neuron terminals include nerve fiber branching that doesn't seem structurally specialized. Molecular mechanisms underlying thermoreception by cells have only just been unraveled. Because temperature is a key factor in channel gating, all neurons and ion channels are susceptible to temperature variations. On the other hand, thermoreceptors are neurons, and thermosensors are rare ion channel types. Perhaps as a result of their distinctive robust adaptation, thermoreceptors are more sensitive to shifts in temperature than to absolute temperature values.
The molecular basis of thermosensitivity: Although the exact process by which temperature affects TRP channels remains unknown, many theories have been put forward:
• A temperature-dependent ligand that binds to a receptor and modulates the channel might be produced.
• A shift in the channel's structural composition caused by temperature variations might cause it to open.
• Shifts in temperature can influence ion channel function by altering membrane shape and tension.
Given that capsaicin is considered to cause a burning sensation, it has been speculated that heat and capsaicin may share the same pathway to activate TRPV1 and generate discomfort. The excised patches are affected by both stimuli, and it is generally believed that unpleasant heat directly activates TRPV1, making it a real heat sensor.
Sensation Receptors: TRP and TREK
The TREK and TRP channels have previously been shown to be two essential components of the temperature response, and the evidence is strong. As thermosensors in thermoreceptive neurons or keratinocytes, they collect heat experience at the periphery. Conversely, and certainly not less importantly, they enable neurons in the hypothalamus to function as internal thermoreceptors, which aids in regulating internal temperature within the organism.
Overexpression in heterologous systems does not affect the generally low activity of TREK channels at ambient temperature and atmospheric pressure. Although other thermosensitive proteins such as ENaC channels, P2X receptors, and the Na/K ATPase need consideration, researchers feel that this is outside the purview of this study. It seems that many kinds of channels interact to regulate cell thermosensitivity; this has been seen in neurons in the hypothalamus.
Although transient receptor potential (TRP) channels have been traditionally thought of as thermosensors, new research suggests that other channels are required to account for the myriad of processes at work in thermosensation. Furthermore, reception at moderate temperatures and the perception of harmless cold, but not painful cold, seem to be mediated by TREK2 channels. Still, the combined actions of TREK1 and TRAAK may be crucial for the perception of severe cold.
ARA-290 Peptide and TRPV1 Receptors
Studies suggest that to reduce neuropathic pain, ARA-290 may target the innate repair receptor (IRR) to down-regulate inflammation, one of its immunomodulatory and anti-inflammatory properties. Nobody knows whether the analgesic action mediated by ARA 290 is due to this or some other mechanism. The potential of ARA 290 to inhibit or affect pain receptors in the periphery is of special interest to scientists in this investigation. This study used calcium imaging, cell culture, and behavioral testing to learn if ARA 290 may alleviate capsaicin-induced mechanical hypersensitivity by selectively inhibiting TRPV1 channel activity. Research suggests that ARA-290 may inhibit the inflammatory cytokines TNF-a and NF-kB, leading to decreased cell adhesion molecules.
Researchers also looked at how ARA 290 affected leukocyte adhesion behavior, which is a major contributor to microvascular damage and tissue infiltration due to interactions with the endothelium of blood vessels. Hypercoagulability is caused by a combination of events, including the induction of cell adhesion molecules (CAMs) on the endothelium surface and in circulating leukocytes by TNF-α and interleukin (IL)-1β. Hence, it seems reasonable that ARA290's potential to inhibit the TNF-α-driven response might affect the bond between leukocytes and endothelial cells in wounds. The gene expression of two cell CAMs, vascular CAM-1 (CD106) and platelet endothelial CAM-1 (CD31), was evaluated.
In the control group that received a vehicle, TNF-α levels rose quickly in the wound center before dropping sharply at 24 hours, in line with the fast and widespread tissue necrosis in that area. In contrast, at the wound edge, where perfusion was maintained for longer, TNF-α levels peaked at 24 hours and again at 48 hours. In contrast, wounds presented with ARA290 suggested entirely different dynamics, with a gradual increase in TNF-α levels over time rather than an early spike, even though there were extensive cellular infiltrates.
ARA-290 Peptide and Diabetes
Plasma glucose concentrations were speculated to be lower in GK rats who received ARA290 daily for up to four weeks, and there was speculated to be a notable 20% reduction in HbA1c without alterations in insulin sensitivity throughout the body or in the liver. Islets from rats presented with ARA290 appeared to have secreted more insulin when stimulated with glucose.
Acutely accelerated glucose-stimulated insulin secretion, increased ATP generation, and improved glucose oxidation rate were all hypothesized indicators that ARA290 may have improved stimulus-secretion coupling for glucose in GK rat islets.
Investigations purport that when everything else fails, blocking protein kinase may eliminate ARA290's effects on insulin secretion. Finally, diabetic GK rats presented with ARA290 seemed to have improved glucose tolerance independent of hematocrit. This impact seems to be caused by better glucose metabolism and [Ca2+] I handling in β-cells, leading to improved glucose-induced insulin release.
The results implied that ARA290 may reduce neuritic dystrophy by 55–74% compared to untreated diabetic research models or a different group of diabetic mice who were given the peptide at the 4-month mark. Surprisingly, findings implied that ARA290 did not appear to influence the number of ganglionic neurons or the persistence of neuronopathy (pale or degenerating neurons) in Akita diabetic mice during this time.
ARA-290 Peptide and Inflammation
ARA290 was theorized to boost the glomerular filtration rate throughout the seven-day study. Additionally, 15 minutes after perfusion, ARA290 tended to decrease IL-6 and MCP-1 expression. Reduced interstitial fibrosis was speculated seven days after perfusion with ARA290.
Scientists speculate that eNOS phosphorylation might be enhanced by ARA290 and EPO. One possible explanation for ARA290's anti-inflammatory properties and impact on renal function is its possible action on these pathways.
"ARA290 enhanced kidney function. The first twenty-four hours after reperfusion suggested increased plasma creatinine levels across the board. Throughout the subsequent six days after the first day, plasma creatinine levels decreased. There was no difference in plasma creatinine levels or urine flow between the animals given vehicle and those presented with ARA290." Through the cannulated ischemic kidney, the glomerular filtration rate (GFR) of the I/R kidney was determined using 24-hour urine and daily plasma creatinine levels. Following perfusion, ARA290 appeared to significantly raise the I/R kidney's GFR within the first week. Hemoglobin, hematocrit, urea, and aspartate transaminase plasma levels were all within normal ranges.
References
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[iii] Brines, Michael, et al. “ARA 290, a Nonerythropoietic Peptide Engineered from Erythropoietin, Improves Metabolic Control and Neuropathic Symptoms in Patients with Type 2 Diabetes.” Molecular Medicine, vol. 20, no. 1, 13 Mar. 2015, pp. 658–666, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365069/, 10.2119/molmed.2014.00215.
[iv] Muller, Carole, et al. “ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats.” Molecular Medicine (Cambridge, Mass.), vol. 21, no. 1, 1 May 2016, pp. 969–978, pubmed.ncbi.nlm.nih.gov/26736179/, 10.2119/molmed.2015.00267.
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[vi] van Rijt, Willem G., et al. “ARA290, a Non-Erythropoietic EPO Derivative, Attenuates Renal Ischemia/Reperfusion Injury.” Journal of Translational Medicine, vol. 11, 9 Jan. 2013, p. 9, pubmed.ncbi.nlm.nih.gov/23302512/, 10.1186/1479-5876-11-9.
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[ix] Schmidt, Robert E., et al. “Effect of Insulin and an Erythropoietin-Derived Peptide (ARA290) on Established Neuritic Dystrophy and Neuronopathy in Akita (Ins2 Akita) Diabetic Mouse Sympathetic Ganglia.” Experimental Neurology, vol. 232, no. 2, 1 Dec. 2011, pp. 126–135, pubmed.ncbi.nlm.nih.gov/21872588/, 10.1016/j.expneurol.2011.05.025.
[x] Cherian, Leela, et al. “534: EFFICACY OF AN ERYTHROPOIETIN – MIMETIC PEPTIDE (ARA290) IN EXPERIMENTAL TRAUMATIC BRAIN INJURY.” Critical Care Medicine, vol. 42, no. 12, 1 Dec. 2014, p. A1488, journals.lww.com/ccmjournal/Citation/2014/12001/534__EFFICACY_OF_AN_ERYTHROPOIETIN___MIMETIC.501.aspx, 10.1097/01.ccm.0000458031.87762.36.
