Natural molecules as promising players against diabetic peripheral neuropathy: an emerging nutraceutical approach

Figures & data

Figure 1. Diabetes-associated complications.

Figure 2. Schematic diagram of diabetes-associated neuropathies.

Figure 3. Pathways implicated in diabetic peripheral neuropathy.

Figure 4. Treatment strategies for diabetic peripheral neuropathy.

Table 1. Treatment strategies against diabetic peripheral neuropathy.

Drug Class	Mechanism of Action	Reference
Symptomatic Therapy
First-Line Therapy
Amitriptyline Imipramine Desipramine (Tricyclic antidepressant)	Inhibit reuptake of noradrenaline and serotonin	^[Citation35–38]
Duloxetine (Serotonin and Noradrenaline Reuptake Inhibitors)	inhibit the reuptake of noradrenaline and serotonin, augmenting descending inhibitory pathways
Second Line therapy
Tramadol (Opioids)	Inhibit reuptake of serotonin and noradrenaline	^[Citation35–38]
Mechanism-Based Therapy
Aldose Reductase Inhibitors (ARIs)	ARIs prevent the intracellular acquisition of sorbitol and fructose via inhibiting aldose reductase activity	^[Citation39]
Angiotensin-Converting Enzyme Inhibitors (ACEIs)	Angiotensin II acts as a potent vasoconstrictor and also possesses pro-inflammatory properties, ACEIs inhibit angiotensin II and prevent vasoconstriction of blood vessels that prevent further complications of DPN	^[Citation40]
Advanced Glycation End Product Inhibitors (AGEIs)	AGEIs such as Benfotiamine that is a derivative of vitamin B1 (thiamine), suppress tissue AGEs formation and prevent damage caused by oxidative stress in DPN	^[Citation39]
Hexosamine Pathway Inhibitors (HPIs)	HPIs inhibit the activation of the hexosamine pathway and prevent the formation of free radicals	^[Citation41]
bFGF and NGF	Combination therapy of bFGF and NGF inhibits apoptosis of Schwann cells and ameliorates neuropathic pain associated with diabetes	^[Citation42]
NMDA Antagonists	NMDA receptor blocker such as Dextromethorphan (low affinity) blocks NMDA receptors to relieve pain related to DPN	^[Citation39]
Natural Product-Based Therapy
Baicalein	Baicalein alleviates DN via inhibiting p38 MAPK activation and oxidative–nitrosative stress	^[Citation43]
Naringin	Naringin down-regulates free radical formation, tumor necrosis factor-α (TNF-α), apoptosis and causes restoration of membrane-bound phosphate (inorganic) activity to inhibit diabetes-associated neuropathic pain	^[Citation44]
Morin	Morin possesses neuroprotective activity via attenuating reactive oxygen species (ROS) mediated oxidative damage as well as neuro-inflammation in DPN	^[Citation45]
Quercetin	Quercetin causes a reduction in the up-regulation of the P2X4 receptor-stimulated p38-MAPK activation to relieve thermal and mechanical hyperalgesia in DPN	^[Citation46]
Rutin	Rutin enhances Na/K-ATPase activities to increase NCV in sciatic nerves, decreases glucose, and oxidative stress in DPN	^[Citation47]
Chlorogenic Acid	Chlorogenic acid reduces oxidative stress, acts as a modulator of inflammation, inhibits NF-kB translocation	^[Citation48]
Epigallocatechin gallate	EGCG inhibits oxidative stress and acts as ARI	^[Citation49]
Ellagic Acid	Ellagic acid inhibits oxidative stress and NF-κB pathway activation	^[Citation50]
Drug Class for Prevention of DN
Sarpogrelate	↓ Thromboxane A2, ↓ monocyte chemoattractant protein-1	^[Citation51]
Insulin	Insulin induces up-regulation of lipoprotein lipase which gives lipids to the myelin sheath and also helps in the regeneration of the myelin sheath during DPN	^[Citation52]
Benfotiamine	Decreases AGE levels to prevent oxidative stress-induced damage during DPN
C-Peptide	C-peptides attach themselves to G protein-coupled receptor and also Improves blood flow to prevent vasoconstriction
Aspirin	Aspirin as an anti-oxidant reduces oxidative stress in DPN	^[Citation39]

Figure 5. Characteristic features of natural molecules.

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