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Written by - Zhang Zhan, Editor-in-Chief—Sizhen Wang—Xia Ye
radiotherapy is an important adjunct treatment for patients with head and neck tumors such as nasopharyngeal carcinoma, primary or metastatic brain tumors[1], however, radiation therapy can also cause damage to adjacent normal brain tissue, leading to central nervous system complications[2].
。 Radioation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, and its clinical symptoms include brain tissue edema, necrosis and cognitive dysfunction, which seriously affects the quality of life of
patients.
Due to a lack of understanding of the pathogenesis of RIBI[3], clinical treatment options for patients with RIBI are relatively limited
.
Traditionally, corticosteroid and antibodies to vascular endothelial growth factor (VEGF) have been shown to relieve radiation-induced cerebral edema [4,5
].
However, due to the high recurrence rate and serious adverse effects of these two treatments, there is an urgent need to develop new RIBI's treatment interventions
.
On September 21, 2022, a research team led by Professor Tang Yamei of the Department of Neurology and Brain Science Research Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University published a research team entitled "Pregabalinmitigates Microglial activation and neuronal injury by inhibiting HMGB1" in the Journal of Neuroinflammation The research paper "signaling pathway in radiation-induced brain injury" elucidated the mechanism of action of Pregabalin in inhibiting microglial activation and neuronal damage in RIBIs
.
The authors propose that pregabalin may act on neurons and inhibit the inflammatory pathways of microglia by inhibiting the nuclear translocation and release of neuronal HMGB1 proteins, thereby mitigating microglial activation and neuronal damage
caused by radiation.
This study elucidated the neuroprotective effect of pregabalin in RIBI, providing a strategy for targeting neurons HMGB1 and microglia TLR2/TLR4/RAGE signaling pathways for RIBI
.
Pregabalin is a structural derivative of γ-aminobutyric acid (GABA) and has been developed as a potential first-line treatment for neuropathic pain
.
It binds
to α2-δ subunits of voltage-gated calcium channels (VGCC) in the central nervous system.
Pregabalin significantly reduces Ca2+ influx by blocking VGCC, thereby inhibiting the release
of excitatory neurotransmitters.
There is growing evidence that pregabalin has a neuroprotective effect in spinal cord injury, epilepsy, multiple sclerosis, traumatic brain injury, cerebral ischemia and reperfusion, diabetic retinopathy, fibromyalgia syndrome and other diseases, and its principle of action is still unclear
。 Professor Tang Yamei led the clinical study of post-radiotherapy neuralgia treatment, the clinical trial of pregabalin for neuropathic pain after radiotherapy for head and neck tumors, published online in the Journal of Clinical Oncology on November 20, 2018 [6].
The authors' previous work has demonstrated that pregabalin is effective and safe in the treatment of neuralgia
caused by radiotherapy.
However, it is unclear whether pregabalin exerts neuroprotective effects in RIBI
.
In this study, the authors successfully constructed a mouse model
of RIBI by performing a 30 Gy dose of whole brain irradiation on BALB/c mice.
By referring to the dose used in clinical studies of pregabalin and calculating equivalent dose conversion between animals and humans based on body surface area, a dose of 30 mg/kg is finally selected for animal experimental studies (Figure 1A).
Because the hippocampus is involved in memory formation and cognitive function, the authors first detected that pregabalin in hippocampal tissue can effectively inhibit the expression of inflammatory factors (Figures 1B, C), and observed consistent phenomena in the cerebral cortex (Figures 1D-G).
Previous studies have shown that elevated post-radiation inflammation-related cytokines are mainly related to microglia, and the authors found that pregabalin inhibits radioactivity-induced microglia cell enlargement and increased expression of microglia CD68 (marker for microglia activation) (Figure 1 H-J).
These results (Figure 1) suggest that pregabalin has significant pharmacological effects in inhibiting microglia activation and inflammatory response, and that pregabalin may have potential value
in alleviating RIBI.
Figure 1 Pregabalin inhibits microglial activation and inflammatory response in RIBI mice (Credit: Zhang Z, et al.
, J Neuroinflammation, 2022)
There is growing evidence that microglial activation-mediated inflammatory responses contribute to nerve damage and neurodegenerative diseases
。 The authors cleverly constructed an in vitro study model, starting with incubation of neurons using culture supernatants of repulsed BV2 microglia receiving radiation (Figure 2A), and MAP2 immunofluorescence staining showed a decrease in the number of neuronal dendrites, suggesting that irradiated microglia produce inflammatory cytokines that may lead to neuronal damage (Figures 2B, C).
。 Interestingly, the authors continued incubation of BV2 cells in the post-injury neuronal culture supernatant, which accidentally triggered the inflammatory response of microglia (Figure 2D), so there is an amplifying cycle effect between post-radiation microglial inflammation and neuronal damage (Figure 2E), which may be a potential mechanism for
patients with radiation brain injury to worsen over time.
Figure 2 Pregabalin protects neurons from microglia-mediated damage after radiation (Source: Zhang Z, et al.
, J Neuroinflammation, 2022)
In animal experiments, researchers have determined that pregabalin can alleviate neuronal apoptosis and loss
in RIBI mice 。 In order to further explore the protective effect of pregabalin on radiation-induced neuroinflammation and brain damage, the researchers studied the interaction between cells through in vitro coculture and cell supernatant incubation, screened the cell types of pregabalin in the brain, and finally determined that it can act on neurons to inhibit microglial inflammation and neuronal damage (Figure 2 F-K).
By screening the cytokines released by neurons and a series of knockout verification experiments, the authors finally determined that pregabalin can inhibit the nucleation and secretion of neuronal HMGB1, block the activation of HMGB1-mediated microglia TLR2/TLR4/RAGE-NF-κB inflammatory signaling pathways, thereby inhibiting the production of inflammatory cytokines such as IL-6, IL-1β and TNF-α, and ultimately exerts neuroprotective effects (Figure 3).
。
Figure 3 Schematic diagram of the mechanism of pregabalin in inhibiting RIBI's small glial cell activation and neuronal damage (Source: Zhang Z, et al.
, J Neuroinflammation, 2022)
Article conclusion and discussion, inspiration and prospect This study reveals that pregabalin by inhibiting HMGB1-TLR2/TLR4/ The RAGE signaling pathway mitigates microglia inflammation and neuronal loss, demonstrating the mechanism of protective action of the drug against radiation brain injury (RIBI) (Figure 3
).
Pregabalin may be a safer and more promising strategy for early intervention in RIBI compared to other treatment strategies
.
Given the important role of pregabalin in regulating microglial activation and neuroinflammation in RIBI, the potential use of pregabalin in other neurodegenerative diseases deserves further study
.
The precise molecular mechanism by which pregabalin inhibits HMGB1 nuclear translocation in neurons also needs to be elucidated
by further studies.
References (swipe up and down) [1]Owonikoko TK, Arbiser J, Zelnak A, Shu HK, Shim H, Robin AM, Kalkanis SN, Whitsett TG, Salhia B, Tran NL, et al.
Current approaches to the treatment of metastatic brain tumours.
Nat Rev Clin Oncol.
2014; 11:203–22.
[2] Cheung MC, Chan AS, Law SC, Chan JH, Tse VK.
Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma.
Cancer.
2003; 97:2019–26.
[3] Wilke C, Grosshans D, Duman J, Brown P, Li J.
Radiation‑induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults.
Neuro Oncol.
2018; 20:597–607.
[4] Robbins M, Greene Schloesser D, Peiffer A, Shaw E, Chan M, Wheeler K.
Radiation induced brain injury: A review.
Front Oncol.
2012; 2:8.
[5] Jeyaretna DS, Curry WT Jr, Batchelor TT, Stemmer‑Rachamimov A, Plotkin SR.
Exacerbation of cerebral radiation necrosis by bevacizumab.
J Clin Oncol.
2011; 29:e159‑162.
[6] Jiang J, Li Y, Shen Q, Rong X, Huang X, Li H, Zhou L, Mai HQ, Zheng D, Chen MY, et al.
Effect of pregabalin on radiotherapy related neuropathic pain in patients with head and neck cancer: a randomized controlled trial.
J Clin Oncol.
2019; 37:135–43.
radiotherapy is an important adjunct treatment for patients with head and neck tumors such as nasopharyngeal carcinoma, primary or metastatic brain tumors[1], however, radiation therapy can also cause damage to adjacent normal brain tissue, leading to central nervous system complications[2].
。 Radioation-induced brain injury (RIBI) is the most serious complication of radiotherapy in patients with head and neck tumors, and its clinical symptoms include brain tissue edema, necrosis and cognitive dysfunction, which seriously affects the quality of life of
patients.
Due to a lack of understanding of the pathogenesis of RIBI[3], clinical treatment options for patients with RIBI are relatively limited
.
Traditionally, corticosteroid and antibodies to vascular endothelial growth factor (VEGF) have been shown to relieve radiation-induced cerebral edema [4,5
].
However, due to the high recurrence rate and serious adverse effects of these two treatments, there is an urgent need to develop new RIBI's treatment interventions
.
On September 21, 2022, a research team led by Professor Tang Yamei of the Department of Neurology and Brain Science Research Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University published a research team entitled "Pregabalinmitigates Microglial activation and neuronal injury by inhibiting HMGB1" in the Journal of Neuroinflammation The research paper "signaling pathway in radiation-induced brain injury" elucidated the mechanism of action of Pregabalin in inhibiting microglial activation and neuronal damage in RIBIs
.
The authors propose that pregabalin may act on neurons and inhibit the inflammatory pathways of microglia by inhibiting the nuclear translocation and release of neuronal HMGB1 proteins, thereby mitigating microglial activation and neuronal damage
caused by radiation.
This study elucidated the neuroprotective effect of pregabalin in RIBI, providing a strategy for targeting neurons HMGB1 and microglia TLR2/TLR4/RAGE signaling pathways for RIBI
.
Pregabalin is a structural derivative of γ-aminobutyric acid (GABA) and has been developed as a potential first-line treatment for neuropathic pain
.
It binds
to α2-δ subunits of voltage-gated calcium channels (VGCC) in the central nervous system.
Pregabalin significantly reduces Ca2+ influx by blocking VGCC, thereby inhibiting the release
of excitatory neurotransmitters.
There is growing evidence that pregabalin has a neuroprotective effect in spinal cord injury, epilepsy, multiple sclerosis, traumatic brain injury, cerebral ischemia and reperfusion, diabetic retinopathy, fibromyalgia syndrome and other diseases, and its principle of action is still unclear
。 Professor Tang Yamei led the clinical study of post-radiotherapy neuralgia treatment, the clinical trial of pregabalin for neuropathic pain after radiotherapy for head and neck tumors, published online in the Journal of Clinical Oncology on November 20, 2018 [6].
The authors' previous work has demonstrated that pregabalin is effective and safe in the treatment of neuralgia
caused by radiotherapy.
However, it is unclear whether pregabalin exerts neuroprotective effects in RIBI
.
In this study, the authors successfully constructed a mouse model
of RIBI by performing a 30 Gy dose of whole brain irradiation on BALB/c mice.
By referring to the dose used in clinical studies of pregabalin and calculating equivalent dose conversion between animals and humans based on body surface area, a dose of 30 mg/kg is finally selected for animal experimental studies (Figure 1A).
Because the hippocampus is involved in memory formation and cognitive function, the authors first detected that pregabalin in hippocampal tissue can effectively inhibit the expression of inflammatory factors (Figures 1B, C), and observed consistent phenomena in the cerebral cortex (Figures 1D-G).
Previous studies have shown that elevated post-radiation inflammation-related cytokines are mainly related to microglia, and the authors found that pregabalin inhibits radioactivity-induced microglia cell enlargement and increased expression of microglia CD68 (marker for microglia activation) (Figure 1 H-J).
These results (Figure 1) suggest that pregabalin has significant pharmacological effects in inhibiting microglia activation and inflammatory response, and that pregabalin may have potential value
in alleviating RIBI.
Figure 1 Pregabalin inhibits microglial activation and inflammatory response in RIBI mice (Credit: Zhang Z, et al.
, J Neuroinflammation, 2022)
There is growing evidence that microglial activation-mediated inflammatory responses contribute to nerve damage and neurodegenerative diseases
。 The authors cleverly constructed an in vitro study model, starting with incubation of neurons using culture supernatants of repulsed BV2 microglia receiving radiation (Figure 2A), and MAP2 immunofluorescence staining showed a decrease in the number of neuronal dendrites, suggesting that irradiated microglia produce inflammatory cytokines that may lead to neuronal damage (Figures 2B, C).
。 Interestingly, the authors continued incubation of BV2 cells in the post-injury neuronal culture supernatant, which accidentally triggered the inflammatory response of microglia (Figure 2D), so there is an amplifying cycle effect between post-radiation microglial inflammation and neuronal damage (Figure 2E), which may be a potential mechanism for
patients with radiation brain injury to worsen over time.
Figure 2 Pregabalin protects neurons from microglia-mediated damage after radiation (Source: Zhang Z, et al.
, J Neuroinflammation, 2022)
In animal experiments, researchers have determined that pregabalin can alleviate neuronal apoptosis and loss
in RIBI mice 。 In order to further explore the protective effect of pregabalin on radiation-induced neuroinflammation and brain damage, the researchers studied the interaction between cells through in vitro coculture and cell supernatant incubation, screened the cell types of pregabalin in the brain, and finally determined that it can act on neurons to inhibit microglial inflammation and neuronal damage (Figure 2 F-K).
By screening the cytokines released by neurons and a series of knockout verification experiments, the authors finally determined that pregabalin can inhibit the nucleation and secretion of neuronal HMGB1, block the activation of HMGB1-mediated microglia TLR2/TLR4/RAGE-NF-κB inflammatory signaling pathways, thereby inhibiting the production of inflammatory cytokines such as IL-6, IL-1β and TNF-α, and ultimately exerts neuroprotective effects (Figure 3).
。
Figure 3 Schematic diagram of the mechanism of pregabalin in inhibiting RIBI's small glial cell activation and neuronal damage (Source: Zhang Z, et al.
, J Neuroinflammation, 2022)
Article conclusion and discussion, inspiration and prospect This study reveals that pregabalin by inhibiting HMGB1-TLR2/TLR4/ The RAGE signaling pathway mitigates microglia inflammation and neuronal loss, demonstrating the mechanism of protective action of the drug against radiation brain injury (RIBI) (Figure 3
).
Pregabalin may be a safer and more promising strategy for early intervention in RIBI compared to other treatment strategies
.
Given the important role of pregabalin in regulating microglial activation and neuroinflammation in RIBI, the potential use of pregabalin in other neurodegenerative diseases deserves further study
.
The precise molecular mechanism by which pregabalin inhibits HMGB1 nuclear translocation in neurons also needs to be elucidated
by further studies.
Original link: https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-022-02596-7
Zhang Zhan, Jiang Jingru and He Yong of the Department of Neurology and Brain Science Research Center of Sun Yat-sen Memorial Hospital of Sun Yat-sen University are the co-first authors of the paper, and Tang Yamei, Lin Weijie and Li Yi are the co-corresponding authors
of the paper.
[1] Trailer | Conference on Neuromodulation and Brain-Computer Interface (U.
S.
Pacific Time: October 12-13), Beijing Time[
2] Conference Report - The human brain and machine are gradually approaching, and the "black technology" of brain-computer interfaces shines into reality
References (swipe up and down) [1]Owonikoko TK, Arbiser J, Zelnak A, Shu HK, Shim H, Robin AM, Kalkanis SN, Whitsett TG, Salhia B, Tran NL, et al.
Current approaches to the treatment of metastatic brain tumours.
Nat Rev Clin Oncol.
2014; 11:203–22.
[2] Cheung MC, Chan AS, Law SC, Chan JH, Tse VK.
Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma.
Cancer.
2003; 97:2019–26.
[3] Wilke C, Grosshans D, Duman J, Brown P, Li J.
Radiation‑induced cognitive toxicity: pathophysiology and interventions to reduce toxicity in adults.
Neuro Oncol.
2018; 20:597–607.
[4] Robbins M, Greene Schloesser D, Peiffer A, Shaw E, Chan M, Wheeler K.
Radiation induced brain injury: A review.
Front Oncol.
2012; 2:8.
[5] Jeyaretna DS, Curry WT Jr, Batchelor TT, Stemmer‑Rachamimov A, Plotkin SR.
Exacerbation of cerebral radiation necrosis by bevacizumab.
J Clin Oncol.
2011; 29:e159‑162.
[6] Jiang J, Li Y, Shen Q, Rong X, Huang X, Li H, Zhou L, Mai HQ, Zheng D, Chen MY, et al.
Effect of pregabalin on radiotherapy related neuropathic pain in patients with head and neck cancer: a randomized controlled trial.
J Clin Oncol.
2019; 37:135–43.
End of article
