20.4

Conclusion

Diabetic neuropathy is a well-established outcome of both types of diabetes. Typi-

cally, diabetic neuropathy affects the toes and distal foot but eventually advances to

include the legs. The toxic effects of hyperglycemia are accepted to be a major factor

in the creation of this complication. Usage of antidepressants, GABA analogues,

opioids, and topical agents to treat pain in PDN is recommended. Currently available

systemic medications provide adequate pain relief for approximately half of affected

patients and are limited by unwanted adverse reactions and multiple-dose regimens.

So, other treatment options need to be explored in need to treat this widespread

complication of diabetes. siRNA demonstrated symptomatic relief in allodynia and

hyperalgesia associated with the downregulation of the P2X3 receptor in the dorsal

root ganglion and many other models. siRNA can be used as potential therapeutics to

treat DPN but are limited by its unstable nature under normal physiology in the blood

wherein it undergoes digestion by nuclease enzymes. So, its encapsulation in novel

Fig. 20.2 Molecular mechanism of siRNA-based nanocarriers in relieving neuropathic pain.

(1) siRNA delivery device enters the cell either through passive or active targeting. Active targeting

is facilitated by the attachment of antibodies or aptamers which enhance the specificity of the

device. (2) The siRNA nanocarrier then enters the cell. (3) The endosome engulfs the delivery

device. (4) Consequently, the outer carrier is degraded to release free siRNA therapeutics. (5) The

siRNA leads to the formation of an RNA-induced silencing complex (RISC). (6) The mRNA and

siRNA interact with each other to progress the knockdown of the desired mRNA. (7) The mRNA is

cleaved through the RISC to silence proteins involved in the pathology of neuropathic pain. (8) The

expression of the P2X7 receptor in the dorsal root ganglion, GluN2B peptide, and the calcitonin

gene-related peptide residing in the spinal cord is inhibited, all of which contribute to alleviating

neuropathic pain and show promise of siRNA nanocarriers as novel therapeutics. siRNA delivery

device alleviates neuropathic pain by inhibition of excitation transmission due to the P2X3 receptor

in the dorsal root ganglion as well as inhibition of expressed calcitonin gene-related peptide housed

in the spinal cord which alters the calcium-augmented pathways in neuropathy pain

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R. Bhandari et al.