Therapeutic Effects of Bee Venom on Immunological and Neurological Diseases

July 2015
Deok-Sang Hwang, Sun Kwang Kim, and Hyunsu Bae

Abstract

Bee Venom (BV) has long been used in Korea to relieve pain symptoms and to treat inflammatory diseases, such as rheumatoid arthritis. The underlying mechanisms of the anti-inflammatory and analgesic actions of BV have been proved to some extent. Additionally, recent clinical and experimental studies have demonstrated that BV and BV-derived active components are applicable to a wide range of immunological and neurodegenerative diseases, including autoimmune diseases and Parkinson’s disease.

These effects of BV are known to be mediated by modulating immune cells in the periphery, and glial cells and neurons in the central nervous system.

This review will introduce the scientific evidence of the therapeutic effects of BV and its components on several immunological and neurological diseases, and describe their detailed mechanisms involved in regulating various immune responses and pathological changes in glia and neurons.

Introduction

Bee Venom (BV) therapy is a form of medicine originated from the ancient Greece and China. Several scientific reports suggesting the anti-rheumatic and anti-inflammatory effects of BV have been published for a hundred years [1,2]. In Korea, BV has long been used to relieve pain and to treat various diseases, such as arthritis, rheumatism, herniation nucleus pulpous, cancer, asthma, and skin diseases [3,4,5]. It is administered systemically or in the form of chemical stimulation of acupoints, so called “BV acupuncture” or “apipuncture”.

BV is known to contain many active components, including peptides (e.g., melittin and apamin), enzymes (e.g., phospholipase A2 (PLA2)), and small molecules (e.g., histamine). Recent studies suggested further that BV and BV-derived active components might have potent therapeutic effects on refractory immunological and neurodegenerative diseases including allergic disorders, autoimmune diseases, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) [3,6,7,8,9], however well-controlled, randomized clinical studies are still insufficient.

In this review, the underlying mechanisms of BV-induced regulation of immune responses as well as of neuronal and glial pathology in refractory immunological and neurological diseases will be discussed, based mainly on the articles that have been published in the last decade.

In addition, the therapeutic effects and mechanisms of BV-derived active components, especially focusing on PLA2, melittin and apamin will be introduced. Finally, we will comment on the future perspectives in the research area of BV therapy.

Conclusions and Perspectives

In this review, we introduced the therapeutic effects of BV and its major components on immunological and neurological diseases, and discussed its underlying mechanisms. We propose that BV is a strong immune modulator that may subsequently affect the CNS glia and neurons.

BV also seems to play a role in maintaining homeostasis in our body’s immune system and nervous system, because BV therapy can regulate two immunologically opposite conditions, i.e., allergic disorders (Th2 dominant) and autoimmune diseases (Th1 dominant).

It remains to be understood how the same treatments of BV or BV-derived active components could modulate both conflicting diseases. Thus, other T cell populations, such as Th17 cells and Tregs, have emerged as a key players in BV-induced modulation of immune and nervous system. Th17 cells are known to play an important role in the pathogenesis of autoimmune, as well as allergic, diseases [46,47].

In contrast, Tregs inhibits activation of both Th1 and Th2 cells, and of Th17 cells, thereby suppressing autoimmune and allergic diseases [11,35]. Indeed, several recent studies reported that BV or bvPLA2 could upregulate peripheral Tregs and/or suppress Th17 responses in various animal models of both diseases [3,8,36,37,48]. Further studies on this issue might shed light on our understandings of such homeostatic therapeutic effects of BV.

In addition, it should be noted that BV is called a “double-edged sword” having nociceptive and anti-nociceptive effects [49], and BV itself could act as a strong allergen. BV induces the release of either of histamine or leukotriene C4 in skin of beekeepers [50], and bvPLA2, the major allergen of BV components [51,52], induces a PLA2-specific IgE immune responses in mice [53], although BV- and bvPLA2-induced Th2 cell immunity and specific IgE production might be protective [54,55].

We also observed that a high dose of BV (2.5 mg/kg, s.c.) treatment could exacerbate oxaliplatin-induced neuropathic pain in rats, whereas low doses of BV (0.25 and 1.0 mg/kg, s.c.) strongly alleviate pain [56]. Thus, the optimal dose and treatment method without side effects should be determined in each disease conditions. Future studies including experimental elucidation of detailed cellular/molecular mechanisms, and well-controlled, randomized clinical trials will lead to a potential therapeutic alternative for treating refractory immunological and neurological diseases.