4.8. Neuronal Regeneration
Neuronal denervation is a key factor that contributes to skeletal muscle loss, and it is related to a plethora of pathological conditions [3,149]. Experimental induction of oxidative stress and inflammation results in skeletal muscle atrophy through induction of denervation e.g., of sciatic nerve [150]. Injuries of peripheral nerves (e.g., sciatic nerve) interrupt mechanical transmission and microvasculation of the nerve and induce reperfusion. Reperfusion involves pooling of oxygen and nutrients promoting high emission of free radicals, which attack protein and lipid contents surrounding the injury site resulting in excessive tissue loss [113]. Likewise, alterations in gut microbiome in aged rats are associated with alterations in serum level of vitamin B12 and fat metabolism as well as reductions in the gastrocnemius muscle mass and sciatic response amplitude [151]. Furthermore, dysregulation of insulin-mediated GLUT4 activity in certain areas of the central nervous system impairs neuronal metabolism and plasticity [69]. Meanwhile, activation of PGC-1α, a core regulator of mitochondrial content and oxidative metabolism, increases muscle fiber resistance to denervation and atrophy through downregulation of two ubiquitin-ligases involved in the ubiquitin-proteasome pathway: MuRF1 and Atrogin-1 [1,152].
Propolis treatment for four weeks restored gastrocnemius muscle weight and improved functional performance (e.g., walking) in rats with crush injury of the sciatic nerve. Effects of propolis were associated with increased nerve healing and regeneration as depicted by faster healing of the myelin sheath and ultra-structurally normal unmyelinated axons and Schwann cells. Investigations of motor conduction from the sciatic nerve to the gastrocnemius muscle indicated that nerve recovery induced by propolis treatment promoted optimal physical functioning by allowing motor conduction to reach the gastrocnemius muscle [113]. Neuroprotective effects of propolis in motor neurons are documented in the literature. Both kaempferide and kaempferol protected motor neurons against atrophy induced by the toxic copper-zinc superoxide dismutase in amyotrophic lateral sclerosis—a serious neurodegenerative disease that involves selective and progressive loss of motor neurons [65]. In addition, orally administered chrysin (a flavonoid that is copious in propolis) to rats intoxicated by 6-hydroxidopamine showed neuroprotective effects by mitigating neuroinflammation, enhancing levels of neurotrophins and neuronal recovery factors (e.g., brain derived neurotrophic factor and glial cell line-derived neurotrophic factor), and maintaining integrity of dopaminergic neurons resulting in better motor performance [72].
The release of acetylcholine (a neurotransmitter that regulates cognition) at the synaptic cleft of the neuromuscular junction is essential for motor neurotransmission, which controls excitation-contraction coupling and cell size. However, free radicals, cytokines, and AGEs impair neurotransmission by altering the production of acetylcholine [6,21,149,153]. On the other hand, upregulation of acetylcholine receptors improves neurotransmission [154]. Treatment with royal jelly may correct acetylcholine neurotransmission given its high content of acetylcholine (4–8 mM) [60]. In addition, royal jelly, propolis, and bee pollen are rich in antioxidant elements that have a potential to scavenge ROS and mitigate other pathologies that contribute to acetylcholine deficiency (e.g., neuroinflammation) [73,101,102,103]. In this respect, treatment of experimental models of carrageenan-induced hind paw edema with hydroalcoholic extract of red propolis and its biomarker, formononetin, is reported to inhibit leukocyte migration and ameliorate inflammatory neurogenic pain induced by injections of formalin and glutamate [115]. However, investigations of the action of bee products on neurotransmission are very scarce.