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Page 2 of 13 Souza et al. Neuroimmunol Neuroinflammation 2019;6:12 I http://dx.doi.org/10.20517/2347-8659.2019.04

(iNOS) and increase M2 (Arg-1 and TGF-β) phenotypic markers; (4) promote neuroprotection by reducing the death
of neurons and oligodendrocytes; and (5) increase the expression of the anti-apoptotic factor BCL-2.

Conclusion: Apipuncture treatment induces locomotor recovery and neuroprotection after the compression model
of spinal cord injury. Further, it reduces neuroinflammation by decreasing M1 polarization and increasing M2
phenotype.

Keywords: Acupuncture, bee venom, spinal cord injury compression, microglia, macrophage, neuroinflammation

INTRODUCTION
Acupuncture, one of the therapies of Traditional Chinese Medicine based on the stimulation of specific
[1]
body points , has shown positive effects in different experimental models of neurodegenerative diseases
[2]
[4]
[3]
such as Parkinson’s disease (PD) , amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) .
Different modalities of acupuncture points (acupoints) stimulation have been used to improve locomotor
performance, reduce inflammation and promote neuroprotection in SCI models . Bee venom (BV)
[4-7]
acupuncture (apipuncture) is a therapeutic practice that BV (bee sting itself or diluted) is injected into
acupuncture points .
[8,9]
BV is a complex substance with approximately 18 bioactive components, including phospholipase A2,
histamine, norepinephrine, apamin and melittin (its principal component, representing 40%-60% of the BV
total dry extract) [9,10] . The BV therapy (systemic administration of BV at doses generally between 0.1 and
0.5 mg/kg) has anti-nociceptive, anti-tumor, anti-inflammatory and anti-apoptotic effect [9-11] . Although
several mechanisms of action have been implicated in the therapeutic effects of melittin or the other
components of BV, e.g., the anti-arthritis effect of BV has been related to decrease in COX-2 and PLA2
[9]
expression and the decrease in the levels of TNF-α, IL-1, IL-6, NO, and ROS . As BV is a complex
substance, various mechanisms of it still need to be revealed.

When BV is applied in acupoints, it promotes intensification of its effects and more intense and lasting
acupoint stimulation effects [12,13] , which contribute to the clinical improvement of many diseases . BV
[9]
[14]
apipuncture has been used to treat inflammatory diseases such as rheumatoid arthritis and to promote
pain relief in patients with chronic low back pain [10,15] . Besides, it can also be applied as a complementary
therapy to treat PD and ALS in humans [10,11,16] . Unfortunately, the mechanisms involved in the improvement
of nervous system disorders are still poorly understood.

Previous results from our group, using a compression SCI model, showed that apipuncture in ST36 and
GV3 acupoints was able to modulate the balance between pro-inflammatory (IL-6) and anti-inflammatory
(IL-10) cytokines, promoting a reduction of spinal cord tissue loss and improvement of locomotor
[17]
performance . The neuroinflammation generated after a central nervous system (CNS) traumatic event is
one of the most important factors that contribute to neurological losses leading to aggravation of sensory
and motor neurological impairment [18-20] . However, the inflammatory response also promotes benefits,
at certain stages of the inflammatory process, by phagocytizing cellular debris and stimulating tissue
repair [18,21,22] . The duality of the inflammatory response is believed to be associated with the plasticity of
microglia/macrophage polarization status [22-26] .

The profile of microglia/macrophage polarization phenotypes in M1/M2 are initially simplified paradigms
in an attempt to understand the complexity of the inflammatory response [22,25] , in which M1 is described
for presenting a pro-inflammatory profile, by stimulating and secreting inflammatory factors such as