Apitherapy for Parkinson's Disease: A Focus on the Effects of Propolis and Royal Jelly

Abstract

The vast increase of world's aging populations is associated with increased risk of age-related neurodegenerative diseases such as Parkinson's disease (PD). PD is a widespread disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra, which encompasses a wide range of debilitating motor, emotional, cognitive, and physical symptoms. PD threatens the quality of life of millions of patients and their families. Additionally, public welfare and healthcare systems are burdened with its high cost of care. Available treatments provide only a symptomatic relief and produce a trail of noxious side effects, which increase noncompliance. Hence, researchers have recently focused on the use of nutraceuticals as safe adjunctive treatments of PD to limit its progress and associated damages in affected groups. Propolis is a common product of the beehive, which possesses a large number of therapeutic properties. Royal jelly (RJ) is a bee product that is fed to bee queens during their entire life, and it contributes to their high physical fitness, fertility, and long lifespan. Evidence suggests that propolis and RJ can promote health by preventing the occurrence of age-related debilitating diseases. Therefore, they have been used to treat various serious disorders such as diabetes mellitus, cardiovascular diseases, and cancer. Some evolving studies used these bee products to treat PD in animal models. However, a clear understanding of the collective effect of propolis and RJ as well as their mechanism of action in PD is lacking. This review evaluates the available literature for the effects of propolis and RJ on PD. Whenever possible, it elaborates on the underlying mechanisms through which they function in this disorder and offers insights for fruitful use of bee products in future clinical trials.

Figure 1

Schematic summary of events contributing to the development of Parkinson's disease. Multiple factors contribute to increased production of free radicals in age people. Meanwhile, the antioxidant capacity decreases with aging, which is associated with chronic increase of inflammatory markers [12, 14, 23, 24]. Inflammation along with free radicals induces morphological and functional mitochondrial alterations resulting in impaired energy production and more emission of free radicals. Injuries of the gastrointestinal tract caused by pathogens and ingested toxins stimulate the expression of the synaptic protein α-synuclein in enteric neurons. α-Synuclein then moves through the vagus nerve to be seeded in vulnerable neurons in the CNS [–11]. In the meantime, the expression of genes involved in the synthesis of phospholipids of the biomembrane such as iPLA2-VIA decreases whereas microglia and astrocytes get activated and migrate in response to inflammation and auto-oxidation of dopamine, which trigger the expression of pathological genes such as α-synuclein and parkin [18]. As a result, α-synuclein pathology increases causing a widespread of initial seeds of α-synuclein to the vulnerable neighboring neurons. Consequently, continuous accumulation of α-synuclein results in the growth of intracellular tangles to form Lewy bodies inside dopaminergic neurons of the SNC contributing to neuronal dysfunction and death. α-Synuclein pathology moves from the SNC into the other brain regions such as the cortex leading to reduction of serotonergic and cholinergic markers such as serotonin and acetylcholine [11, 25]. Accordingly, PD patients undergo serious motor impairments, which decrease gait speed and increase the risk of fall, in addition to a range of other debilitating cognitive, psychiatric, and gastrointestinal symptoms such as poor cognitive performance, mood dysregulation, depression, sleep disturbance, nausea, and chronic constipation—which altogether lower quality of life and increase disability and mortality [20, 24]. ↑ denotes increase; ↓ denotes decrease; CNS: central nervous system; SNC: substantia nigra pars compacta; PD: Parkinson's disease.

Figure 2

Components of propolis and royal jelly along with their pharmacological activities. Propolis and royal jelly are rich in numerous bioactive elements. Therefore, they express a range of beneficial activities. The key action through which these bee products promote health span stems mainly from their phenolic and flavonoid fractions, which contribute to their strong antioxidant activities. Scavenging free radicals (which activate destructive molecules such matrix metalloproteinases) and enhancing the expression of antioxidant genes promote the suppression of inflammatory responses, thus protecting against cancer, obesity, diabetes, heart disease, neurodegeneration and neurotoxicity, rheumatoid arthritis, and the like.

Figure 3

Various experimental models of Parkinson's disease. Multiple experimental models of PD have been developed. They are distinguished into 3 classes. Environmental models of PD are produced by numerous neurotoxins, which selectively induce dopaminergic neurodegeneration via mechanisms that involve induction of neurodegeneration through increased production of free radicals, inflammation, and mitochondrial dysfunction. Pharmacological models produce clinical manifestations of PD, e.g., catalepsy and dyskinesia without alterations in neuron structure or function—they block dopamine activity. Genetic models are miscellaneous, and they are produced through induction of gene mutations related to dopamine neurotransmission, mitochondrial function, and protein misfolding (α-synuclein). ↑ denotes increase; ↓ denotes decrease; PD: Parkinson's disease; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA: 6-hydroxydopamine; ROS: reactive oxygen species; caspase-3: cysteine-aspartic acid protease 3.

Figure 4

Probable mechanisms through which propolis and royal jelly (RJ) alleviate symptoms of Parkinson's disease. Propolis, RJ, and their compounds alleviate oxidative damage directly by scavenging free radicals through the release of an electron from their phenolic group and indirectly through activation of ERK/MAPK signaling, which deactivates Keap1, the molecule that degrades NRF2 resulting in NRF2 translocation into the nucleus to activate ARE, which stimulates the expression of antioxidant genes such as HO-1. On the other hand, NRF2 and HO-1 prevent the transcription of inflammatory pathways such as NF-κB resulting in less production of inflammatory cytokines. Mitigation of oxidative stress and neuroinflammation is associated with less mitochondrial respiration and less production of apoptotic molecules such as caspase-3 and bax, eventually leading to less neurodegeneration. On the other side, chrysin increased the expression of various neurotrophic factors possibly through its contribution to HO-1 production; however, the detailed mechanism is not clearly understood. RJ also stimulates the expression of cerebral and hippocampal GDNF, possibly through activation of estrogen receptors. GDNF is associated with neuroprotective effects: enhancing the survival and morphological differentiation of midbrain dopaminergic neurons and fostering their affinity for dopamine. All these events prevent neuronal degeneration, maintain intact brain structure, keep proper levels of dopamine and acetylcholine, and eventually improve motor and cognitive symptoms of PD. ↑ denotes increase; ↓ denotes decrease; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; NRF2: nuclear factor erythroid 2; ARE: antioxidant response element; HO-1: heme oxygenease-1; NF-κB: nuclear factor kappa B; TNF-α: tumor necrosis factor alpha; GDNF: glial cell line-derived neurotrophic factor; AIF: apoptosis inducing factor; caspase-3: cysteine-aspartic acid protease 3; bax: bcl-2-associated X protein; SNC: substantia nigra pars compacta; PD: Parkinson's disease.