Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats

Abstract

Diabetes mellitus (DM), a multifaceted metabolic disorder if not managed properly leads to secondary complications. Diabetic peripheral neuropathy (DPN) is one such complication caused by nerve damage that cannot be reversed but can be delayed. Recently, diabetes patients are using dietary supplements, although there remains a general skepticism about this practice. Curcumin (CUR), one such supplement can help prevent underlying low-grade inflammation in diabetes, but it is plagued by poor oral bioavailability. To better understand the role of bioavailability in clinical outcomes, we have tested double-headed nanosystems containing curcumin (nCUR) on DPN. Because CUR does not influence glucose levels, we have also tested the effects of nCUR combined with long-acting subcutaneous insulin (INS). nCUR with or without INS alleviates DPN at two times lower dose than unformulated CUR, as indicated by qualitative and quantitative analysis of the hind paw, sciatic nerve, spleen, and L4−6 spinal cord. In addition, nCUR and nCUR+INS preserve hind paw nerve axons as evident by the Bielschowsky silver stain and intraepidermal nerve fibers (IENF) density measured by immunofluorescence. The mechanistic studies further corroborated the results, where nCUR or nCUR+INS showed a significant decrease in TUNEL positive cells, mRNA expression of NLRP3, IL-1β, and macrophage infiltration while preserving nestin and NF200 expression in the sciatic nerve. Together, the data confirms that CUR bioavailability is proportional to clinical outcomes and INS alone may not be one of the solutions for DM. This study highlights the potential of nCUR with or without INS in alleviating DPN and warrants further investigation.

Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease

“…The FTIR spectra confirmed the presence of amide linkage­(1630 cm-1) in PLGA-GA2 (Figure S1B). Subsequently, CUR-laden PLGA-GA 2 nanoparticles (nCUR) were made on a large scale and freeze-dried following our published protocols. − The z -average size of nCUR was ∼270 (PDI ∼0.25) (Figure S1C) with ∼0.112 mg of CUR entrapped/mg of PLGA-GA 2 , and particles are spherical in shape (Figure S1D).…”

“…Earlier, we demonstrated that nCUR with or without long-acting insulin alleviates STZ-induced diabetic peripheral neuropathy or diabetic kidney disease in rats by modulation of the inflammatory cascade. 24,40 Herein, we have identified an additional role for this potential combination in preventing diabetic retinopathy by inhibiting Piezo1 in the ganglion cell (GCL) and photoreceptor layers.…”

Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein

“…This arrangement introduces numerous pendant carboxylic acid groups along the polymeric backbone . We further demonstrated conjugating a small molecule ligand on P2s; gambogic acid (GA) binds noncompetitively to transferrin receptors. − The linker used in these studies was a short ethylenediamine (2C), effectively conjugating the GA to P2s (Figure ). Ethylenediamine has been utilized as a linker in diverse applications, particularly on the surface of nanoparticles. , …”

“…Dynamic light scattering (DLS) revealed nanoparticle sizes in the range of approximately 260–290 nm, with zeta potentials > ±20 mV, indicative of stable emulsions and therefore less likely to aggregate (Table ). Furthermore, we have previously shown that GA-decorated nanoparticles in this size range are appropriate for oral absorption. − , …”

Modulation of Macrophages Using Nanoformulations with Curcumin to Treat Inflammatory Diseases: A Concise Review

“…Hence, Cur, with its anti-inflammatory and antioxidant properties, has become a promising candidate drug for the treatment of inflammatory diseases. Nonetheless, the therapeutic activity of Cur is limited due to its poor water solubility, fast biological metabolism, and poor bioavailability [ 24 , 25 , 26 , 27 ]. The dose or frequency of administration must be increased to achieve the desired therapeutic effects, which in turn cause adverse reactions to the body.…”