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Page 10 of 13 Souza et al. Neuroimmunol Neuroinflammation 2019;6:12 I http://dx.doi.org/10.20517/2347-8659.2019.04
[50]
our data, Khalil et al. demonstrated that apipuncture is capable of increasing BCL-2 expression in the PD
model.

Despite the limitation of study in not having immunohistochemical analyses, the increase of anti-
apoptotic factor BCL-2 caused by apipuncture can be related to neuroprotection and survival of neurons
[4]
and oligodendrocytes resulting in better sensory and locomotor performance. Choi et al. demonstrated
through the immunohistochemical technique that manual acupuncture in GV26 and GB34 acupoints
reduced caspase-3 expression, increased the expression of neuron markers and oligodendrocytes at
the lesion site, suggesting that greater survival rate of these cells is related to better performance in the
behavioral tests (BBB and Grid Walk test).

The clinical practice of different acupuncture modalities, such as BV acupuncture and EA, has become
increasingly used as a complementary therapy for symptom relief in patients with PD, ALS, and SCI [16,51,52] .
It is noteworthy that in apipuncture, the BV causes a local “irritation” at the acupoints producing a more
[8,9]
intense and lasting effect than the simple needling . In this experimental protocol, the BV was used in a
very low dose, with this purpose [12,13] . The ST36 and GV3 acupoints were chosen from the combination of
other acupoints that were more efficient in promoting the improvement of locomotor behavior in the SCI
model (unpublished data).

The exact mechanism involved in the anti-inflammatory effects of acupoint stimulation has not yet been
completely elucidated. Currently, it has been postulated the stimulation of acupuncture points acts through
the autonomic nervous system, transmitting signals via the vagus nerve and promoting anti-inflammatory
[53]
responses . In experimental models of peripheral inflammation, such as sepsis and rheumatoid arthritis,
acupuncture increases vagus nerve activity through a mechanism known as “cholinergic anti-inflammatory
[54]
reflex” . The stimulation of acupoints activates sensory inputs that are propagated by Aδ and C fibers,
resulting in the activation of different brain nuclei involved with peripheral vagal tone regulation and
[54]
increase of ACh release . In macrophages, ACh down-regulates the NF-Kb pathway by stimulation
alpha-7 nicotinic receptor, partially attenuating the inflammatory response. In the present study, the role of
vagal activity was not investigated, although it could contribute to the lower macrophage infiltration from
the peripheral circulation [6,54] . The physiological mechanisms of acupuncture in the SCI models are still
uncertain with many questions that need to be clarified. One of the intriguing points about it is that SCI
lesion per se does not seem to block the ascending propagation of the neuronal signal produced by acupoint
stimulation (once in some studies, including ours, the acupoints used is located below the SCI lesion).
Therefore, further studies will be needed to clarify these questions.

In conclusion, despite some limitations, our results indicate that apipuncture may modulate the
neuroinflammatory response via alteration of M1/M2 polarization status, in addition to increasing the
apoptotic factor and promoting neuroprotection, which may in part contribute to a reduction in locomotor
sequelae in the compression SCI model. Thus, we believe that apipuncture may be a potential therapeutic
target as a complementary therapy for the treatment of spinal cord injury.

DECLARATIONS
Acknowledgments
We are indebted to Mr. Ipojucan Pereira de Souza for technical assistance.

Authors’ contributions
Made substantial contributions to conception and design of the study: Souza RN, Medeiros MA
Performed data analysis and interpretation: Souza RN, Monteiro LRN, Medeiros MA.