## 2 Results
### Results of Individual Studies
#### 2.2.2 Botulinum Toxin Key Effect
 } & & & Hippocampus & & \\  & & & & & & \\ \cline{1  
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Biomarker (CIS)** & **Author** & **Unit Measure** & \multicolumn{2}{c}{**BoNT Key Effect (Outcome)**} & \multicolumn{2}{c}{**Summary**} & \multicolumn{1}{c}{**Overall**} \\ \cline{3-6}  & **Biological Sampling** & **Year** & \multicolumn{2}{c}{**Unit Measure**} & \multicolumn{1}{c}{**Sear Issue (our)**} & \multicolumn{1}{c}{**Sear**} \\ \hline \multirow{7}{*}{Collagm} & Xiong, & & & (\(n=6\))HS-bNT (21) (vs. \(n=6\)) IScontrol: (T1)  
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Biomarker (CIS)** & **Author** & **Unit Measure** & **BusT Key Effect (Outcome)** & **Summary** & **Overall** \\
**Biological Sampling** & **Year** & **Initialism V: region (small subvalencies of the signal fragmental nucleus) & & & \\ \hline \multirow{7}{*}{TN} & \multirow{7}{*}{Wu, 2016 [23]} & & & (\(\theta\) = 0) IN-value vs. (\(t\) = 0) IN-value vs. (\(t\) = 7) mean \(\pm\) SD & **VEVLOW** \\  & & & (\(\theta\) = 0) IN-value-Peripheral IoWT (\(\Omega\) / 10 U) vs. (\(\pi\) = 6) & 17 (\(\Omega\) = 7) days after IoWT (\(\Omega\)) & **0**0**0**000 \\  & & & TN-value-wise-Tripheral IoWT (\(\Omega\) / 10 U) vs. (\(\pi\) = 6) & (71) 7 days after IoWT (\(\Omega\)) & **0**0**000 \\  & & & TN-value-wise-Tripheral IoWT (\(\Omega\)) & (\(\phi\) = 0) IN-NR & & \\ \hline \multirow{7}{*}{TN} & \multirow{7}{*}{[PERSON], 2017 [33]} & & \multicolumn{2}{c}{Local worst \(\sigma\)/apli} \\  & & & & AEW vs. sham (T1) (\(\Omega\) = 5414, \(\pi\) = 0.0003) & 1 7 (\(\Omega\) = 52) mean \(\pm\) SD  
Two studies in trigeminal neuralgia, induced by either IoNC or compression of the trigeminal nerve root, demonstrated significant ipsilateral reduction of the upregulated proinflammatory cytokine IL-6 after BoNT treatment when compared to vehicle saline, in TG and TNC [14; 17]. The CX3 CR1 protein level did not differ in a trigeminal neuralgia model before or after BoNT treatment [16], but it was reported that the mRNA expression of this chemokine receptor selectively expressed in microglia was upregulated in scenarios of depression induced by chronic administration of reserpine in a Parkinson disease model, which was significantly decreased in the hippocampus in the experimental group using BoNT [18]. This suggested that the toxin may alleviate microglial activation via interaction with receptors on microglia. Two other studies in trigeminal pain induced by IoNC or Complete Freund's Adjuvant (CFA) observed a significant reduction in induced dural protein extravasation [20; 28]; however, the bilateral effect (ipsilateral and contralateral side) after BoNT was controversial. Collagen-related proteins (I,III), TGF-81, \(\alpha\)-SMA, and myosin II proteins were only measured in two studies inducing hypertrophic scars, and both supported that BoNT injection into tissues from the ears of rabbits remarkably reduced the expression of these biomarkers. TRPA1 protein expression was also found to be increased in models of trigeminal neuropathy induced by IoNC and chronic dry skin itch evoked by acetone-diethyletter-water (AEW), which were significantly inhibited following BoNT administration. The majority of data for single experiments found that BoNT significantly altered the biomarkers' under/over-expression evoked by the investigated disease models and had no effect when the levels of these biomarkers were not changed by the induced chronic conditions in animals. There were a few exceptions: (1) when the toxin influenced the expression of the biomarkers that showed no significant differences between sham and disease model groups (e.g., TLR1, TLR4, TLR8); (2) when BoNT had no effect on the levels of biomarkers that were down/upregulated by the disease model (e.g., IgE, Nav 1.6, 1.8, ATF3, TRPM8); (3) when the effect of the toxin on the altered levels of the biomarkers was unclear (e.g., NR2A, TLR11).