Biochemical and Biophysical Research Communications 526 (2020) 553e559
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications
journal homepage: www.elsevier.com/locate/ybbrc
Minocycline alleviates NLRP3 inflammasome-dependent pyroptosis in
monosodium glutamate-induced depressive rats
Feng Yang a, 1, Wen Zhu a, 1, Xiaofang Cai b, Wen Zhang a, Zhonghai Yu b, Xiangting Li a,
Jingsi Zhang c, Min Cai a, Jun Xiang a, **, Dingfang Cai a, *
a
Department of Integrative Medicine, Zhongshan Hospital, Fudan University, China; Institute of Neurology, Academy of Integrative Medicine, Fudan
University, Shanghai, China
Department of Traditional Chinese Medicine, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University, China
c
Department of Neurology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 February 2020
Accepted 24 February 2020
Available online 1 April 2020
Background: Inflammasome activation and followed by the release of proinflammatory cytokines play a
pivotal role in the development and progression of depression. However, the involvement of gasdermin
D (GSDMD)-mediated pyroptosis in inflammasome-associated depression has not been studied. The
present study aimed to determine the involvement of pyroptosis in the development of depression.
Methods: The rat depressive model was established by the administration of monosodium glutamate
(MSG) in postnatal rats. Minocycline (an anti-inflammatory agent) and VX-765 (a specific inhibitor of
caspase-1) were given as intervention treatments when rats were two-month-old. Rat depressive behaviors were evaluated by behavioral tests, including open field test, sucrose preference test, and forced
swim test. Rat hippocampi were collected for western blotting and immunofluorescence examination.
Results: MSG administration induced depressive-like behavior in rats. MSG upregulated protein presences of caspase-1, GSDMD, interleukin-1b (IL-1b), interleukin-18 (IL-18), NLR pyrin domain-containing 3
(NLRP3), apoptosis-associated speck-like protein (ASC), high mobility group box 1 protein (HMGB1), and
the receptor for advanced glycation end products (RAGE) in the hippocampus. Protein presences of
HMGB1, NLRP3 and GSDMD were upregulated in Olig2þ oligodendrocytes in the hippocampus. The data
suggest that both HMGB1/RAGE/NLRP3 signalings and GSDMD-dependent pyroptosis were activated.
Both minocycline and VX-765 treatments improved depressive-like behaviors. Minocycline treatment
significantly reduced both HMGB1/RAGE/NLRP3 inflammasome signalings and GSDMD-dependent
pyroptosis. VX-765 downregulated GSDMD-dependent pyroptosis, but not HMGB1/RAGE signalings,
indicating that GSDMD-dependent pyroptosis is a key player in the progress of depression.
Conclusion: In rats hippocampus, NLRP3 inflammasome activates GSDMD mediated-pyroptosis in the
hippocampus of MSG-induced depressive rats.
© 2020 Published by Elsevier Inc.
Keywords:
Depression
Pyroptosis
GSDMD
NLRP3 inflammasome
Minocycline
1. Introduction
Major depressive disorder is a mental illness that affects
* Corresponding author. Department of Integrative Medicine, Zhongshan Hospital, Fudan University, China; Institute of Neurology, Academy of Integrative Medicine, Fudan University, Fenglin Road 180, CN-200032, Shanghai, China.
** Corresponding author. Department of Integrative Medicine, Zhongshan Hospital, Fudan University, China; Institute of Neurology, Academy of Integrative Medicine, Fudan University, Fenglin Road 180, CN-200032, Shanghai, China.
E-mail addresses: xiang.jun@zs-hospital.sh.cn (J. Xiang), dingfang_cai@sina.com
(D. Cai).
1
These authors contributed equally.
https://doi.org/10.1016/j.bbrc.2020.02.149
0006-291X/© 2020 Published by Elsevier Inc.
approximately 300 million people worldwide [1,2]. Both physiological and/or psychological changes are about to trigger the onset
of depression [3], leading to psychosocial dysfunction and reduced
life quality. Although many advances have been made in antidepressant treatment, nearly 80% of patients experience recurrences,
at least one episode, in their lifetime [1]. Thus, a better understanding of the underlying mechanism is urgent.
Chronic neuroinflammation is essential for the progress of
depression since elevated inflammatory responses in the central
nervous system are often observed in recurrent stages [4]. Several
inflammation-related mechanisms have been proposed under
pathophysiological conditions, especially mental disorders. The
554
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
involvement of inflammasome is reported in microglia in the
progress of penetrating ballistic-like brain injury, epithelial cells in
the progress of allergic asthma, and endothelial cells in the progress
of type 2 diabetes [5e7]. By binding the receptor for advanced
glycation end products (RAGE), high mobility group box 1 protein
(HMGB1) promotes the activation of NLRP3 inflammasome [8,9],
which is composed of NLR pyrin domain-containing 3 (NLRP3),
apoptosis-associated speck-like protein (ACS), and pro-caspase-1
protein. Pyroptosis is a newly identified form of programmed cell
death characterized by a rapid occurrence of plasma-membrane
rupture mediated by gasdermin D (GSDMD) protein [10,11]. The
activation of pyroptosis is reported in tubular epithelial cells in
acute kidney injury, neurons in subarachnoid hemorrhage, and
monocytes in rheumatoid arthritis [12e14]. Whether these two
inflammatory signals are dependent or not in the process of
depression is unclear. Therefore, the present study was aimed to
investigate the participation of inflammasome and pyroptosis in
the progress of the depressive disorder. Minocycline hydrochloride,
an inhibitor of inflammasome [15] and VX-765, a specific inhibitor
of caspase-1 [16,17], were employed as intervention therapies to
investigate the underlying mechanisms.
2. Materials and methods
2.1. Animals
Newborn (5e8g) Sprague Dawley (SD) rats were housed in the
animal facility (Zhongshang Hospital). The animal room had a 12-h
light/dark cycle (lights on at 7:00 a.m. and off at 7:00 p.m.), and the
room temperature was kept at 22 ± 1 C with consistent humidity
(55 ± 5%). Rats were allowed free access to food and water. The
present experimental procedures were approved by the Animal
Care and Use Committee of Zhongshan Hospital Fudan University
(2018e002).
2.2. Experimental design
In the present study, the depressive rats were induced by
monosodium glutamate (MSG, Sigma-Aldrich St. Louis, MO) [18]. In
brief, MSG (4 mg/kg/day) was administrated subcutaneously in
newborn SD rats during the first five postnatal days, while control
puppets were given saline. Two months later, only male rats were
kept to carry on behavioral tests. After their behavioral tests, all rats
were sacrificed under deep anesthesia for sample collection
(Fig. 1A).
Intervention therapy 1. Effect of minocycline on depressive-like
behaviors. When male rats were two months old, minocycline
(50 mg/kg/day, Aladdin, Shanghai, China) was administrated in
both control and MSG rats via i.p. for four weeks [15] (Fig. 1B).
Intervention therapy 2. Effect of VX-765 on depressive-like behaviors. When male rats were two months old, VX-765 (200 mg/kg/
day, Selleck, Houston, TX) was administrated in MSG rats via i.p. for
four weeks [19,20] (Fig. 1C).
switched every 12 h. After 18-h water deprivation, both water and
sucrose were presented to the rats. The consumption of water and
sucrose solution was recorded for 6 h.
Forced swimming test. The test was conducted with a 15-min
pretest and a 6-min test on the second day. The rats were placed
in a pyrex glass cylinders (height 60 cm, diameter 20 cm) filled with
25 ± 1 C water. The results were expressed as the duration that the
rats presented immobile in the test. Prolonged immobility time was
considered as a depressive-like behavior.
2.4. Western blot analysis
Hippocampal tissues were homogenized in RIPA buffer with
protease inhibitors (Beyotime, Shanghai, China). Protein samples
(50 mg) were loaded in 12% SDS-PAGE gels and transferred to a
0.22 mm polyvinylidene fluoride membrane. After blocking with 5%
nonfat milk, membrane was incubated with primary antibodies:
rabbit polyclonal anti-GSDMD (1:1000, Novus, Minneapolis, MN),
rabbit polyclonal anti-IL-1b (1:1000, ABclonal, Wuhan, Hubei,
China), rabbit polyclonal anti-IL-18 (1:1000, Novus, Minneapolis,
MN), rabbit polyclonal anti-NLRP3 (1:1000, Novus, Minneapolis,
MN), goat polyclonal anti-Olig2 (1:500, Novus, Minneapolis, MN),
rabbit polyclonal anti-caspase-1 (1:1000, Servicebio, Wuhan,
Hubei, China), mouse monoclonal anti-ASC (1:200, Santa Cruz,
Dallas, TX), rabbit polyclonal anti-HMGB1 (1:1000, CST, Danvers,
MA), rabbit polyclonal anti-RAGE (1:1000, Abcam, Cambridge, UK),
and rabbit monoclonal anti-GAPDH (1:5000, ProteinTech, Wuhan,
Hubei, China) in a cold room overnight. Target bands were detected
by enhanced chemiluminescence kits (Millipore, Billerica, MA) and
analyzed via Quantity One software.
2.5. Immunofluorescence examination
Sample slides were prepared in 6-mm thickness. The slides were
incubated in citrate buffer (pH 6.0) for high-temperature antigen
retrieval. The slides were blocked in 10% BAS (Sigma-Aldrich, St.
Louis, MO) at room temperature for 1 h. All slides were incubated
with primary antibodies anti-GSDMD (1:100, Novus, Minneapolis,
MN), anti-Olig2 (1:50, Novus, Minneapolis, MN), anti-HMGB1
(1:200, CST, Danvers, MA), or anti-NLRP3 (1:100, Novus, Minneapolis, MN) in a cold room overnight. Images were observed and
captured with an Olympus microscope (DP71, Olympus).
2.6. Statistical analysis
All data were analyzed using SPSS software (Version 16.0) and
were presented as means ± standard deviation (SD). Data were
analyzed by an independent-sample T-test or one-way analysis of
variance (ANOVA) with post-hoc comparisons of LSD when appropriate. A p-value less than 0.05 was defined as statistical
significance.
3. Results
2.3. Behavioral tests
3.1. MSG induces depressive-like behavior in rats
Open field test. An open field test was used to access locomotor
activity [15]. A clear Plexiglass box (100 *100 *40 cm) with a video
recording system (Shanghai Mobile Datum Information Technology
Company, Shanghai, China) was used. Before recording, the rats
were allowed to explore around in the box for 5 min under dim
light. Rat movements in the plexiglass box were recorded for 5 min.
Sucrose preference test. The rats were acclimated with two
bottles of water for 24 h, followed by two bottles of 1% sucrose
solution for another 24 h. To avoid site preference, the bottles were
After exposure to MSG, two-month-old SD rats were examined
by a series of neurobehavioral tests (Fig. 1A). In the open field test,
control rats explored both central and peripheral areas, whereas
MSG rats spent less time in the central area and had longer latency
time. Compared with control rats, MSG rats had significantly less
walking distance in total and in the central area (Fig. 1DeH).
Compared with control rats, MSG rats took fewer sucrose drinks in
the sucrose preference test (Fig. 1I). In the forced swimming test,
MSG rats were reluctant to move in the swimming pool and had
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
555
Fig. 1. MSG induces depressive-like behavior in rats. A-C The experimental protocol. D The representative tracing of rats in the open field test. E Center time spent in the open field
test (n ¼ 6). F Latency time spent in the open field test (n ¼ 6). G Center distance traveled in the open field test (n ¼ 6). H Total distance traveled in the open field test (n ¼ 6). I
Sucrose consumption in the sucrose preference test (n ¼ 6). J Immobility time spent in the forced swimming test (n ¼ 6). K-T Representative blot (upper panel) and quantitive
analyses (lower panel) of protein expressions of HMGB1 (K), RAGE (L), NLRP3 (M), pro-caspase-1 (N), ASC (O), caspase-1 (P), GSDMD (Q), Olig2 (R), IL-1b (S), and IL-18 (T) n ¼ 4 All
data are expressed as means ± SD, *p < 0.05, compared to saline rats.
556
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
significantly longer immobility time when compared with control
rats (Fig. 1J).
3.2. Both inflammasome signaling and pyroptosis are activated the
hippocampus of MSG rats
MSG stimulation increased HMGB1 and RAGE protein expression in the hippocampus of depressive rats. MSG stimulation also
increased expressions of NLRP3, pro-caspase-1, and ASC protein in
the hippocampus compared to the control group (Fig. 1K-O).
MSG exposure significantly increased caspase-1 and GSDMD
protein expressions, compared to the control group. Protein levels
of IL-1b and IL-18, two major pyroptosis-related inflammatory cytokines, were significantly increased in the hippocampus of the
MSG group (Fig. 1PeT).
3.3. Minocycline ameliorates depressive-like behavior through
downregulation of HMGB1/RAGE/NLRP3 inflammasome and
pyroptosis signalings
To investigate the participation of inflammasome, minocycline,
an inhibitor of inflammasome [15], was used in the study (Fig. 1B).
In the open field test, compared with MSG stimulation,
minocycline-treated rats explored both central and peripheral
areas (Fig. 2A). The minocycline-treated rats spent more extended
time in the central area and had less latency time. Minocycline
treatment significantly improved rats walking distance, both in the
whole area and in the central area (Fig. 2BeE). The minocyclinetreated rats took more sucrose drinks in the sucrose preference
test, which was comparable with control groups (Fig. 2F). In the
forced swimming test, minocycline rats were more active in the
swimming pool and had less immobility time when compared with
MSG rats (Fig. 2G).
Minocycline treatment did not have additional effects on control
rats.
In line with the upregulation of HMGB1, immunofluorescence
revealed that the presence of HMGB1 protein was mainly distributed in the dentate gyrus (DG) region, but not CA1 or CA3 region, of
the hippocampus in MSG rats (Fig. 3A). The protein presence of
HMGB1 was co-localized with Olig2þ oligodendrocytes, while the
signal of Olig2 was significantly increased as well (Fig. 1R). Minocycline treatment reduced both HMGB1 and NLRP3 expressions in
the hippocampus, especially in DG regions, in MSG treated rats
(Fig. 3A and B). Consistently, minocycline treatment reduced
HMGB1, RAGE and NLRP3, pro-caspase-1 and ASC expressions in
rats’ hippocampus (Fig. 3CeG).
Minocycline treatment significantly reduced the protein presence of GSDMD, which was also co-localized with Olig2þ cells in
the DG region of hippocampi. Minocycline treatment markedly
reduced protein expressions of caspase-1, IL-1b and IL-18 in the
hippocampus when compared with the MSG group (Fig. 3HeM).
3.4. VX-765 ameliorates depressive-like behavior through
downregulation of pyroptosis signaling
To investigate the participation of pyroptosis, a specific inhibitor
of caspase-1 VX-765 [16,17], was used in the present study as well
(Fig. 1C). Compared with MSG stimulation, VX-765 treated rats
increased their center time and decreased the latency time in the
open field test. VX-765 treatment significantly improved the center
distance and total distance, when compared with MSGadministrated depressive rats (Fig. 4AeE). Rats in VX-765 group
exhibited increased uptakes of sucrose drink (Fig. 4F) and
decreased immobility time in the forced swimming test when
compared with MSG rats (Fig. 4G).
VX-765 treatment significantly reduced the pyroptosis-related
protein expressions of caspase-1, GSDMD, IL-1b, and IL-18, but
not HMGB1 or RAGE (Fig. 4H-M).
4. Discussion
The present study reports that MSG exposure to neonatal rats
induces depression in their adulthood. The depressive-like behaviors are attributed to the upregulation of inflammasome signalings
and GSDMD-mediated pyroptosis in the oligodendrocytes of rat
hippocampi. Minocycline treatment inactivates NLRP3 inflammasome, blocks pyroptosis in oligodendrocytes, and ameliorates
depression in rats.
Glutamate is an excitatory neurotransmitter. In the present
study, neonatal rats exposed to MSG, a natural form of glutamate
acid, exhibited a lower score in behavioral tests, shown as less
active in physical activities as well as fewer interests in exploring
novel objects, indicating that MSG successfully induces depressive
disorder in SD rats [18,21].
The involvement of neuroinflammatory responses in the
depressive disorder has been well studied [22,23]. In the present
study, MSG exposure increased the protein expressions of the
NLRP3 inflammasome in rats hippocampi, suggesting that the
inflammasome takes part in the depression [23,24]. Since the
protein presence of NLRP3 was colocalized with oligodendrocytes,
it suggests that oligodendrocytes are activated in the
inflammasome-mediated response. Consistently, the upstream
signalings of HMGB1/RAGE were upregulated in oligodendrocytes
as well in the MSG-stimulated hippocampi, confirming the vital
role of oligodendrocytes in the present study. Minocycline treatment downregulated HMGB1/RAGE expression and its
Fig. 2. Minocycline ameliorates depressive-like behavior. A The representative tracing of rats in the open field test. B Center time spent in the open field test (n ¼ 6). C Latency time
spent in the open field test (n ¼ 6). D Center distance traveled in the open field test (n ¼ 6). E Total distance traveled in the open field test (n ¼ 6). F Sucrose consumption in the
sucrose preference test (n ¼ 6). G Immobility time spent in the forced swimming test (n ¼ 6). All data are expressed as means ± SD, *p < 0.05 compared to saline rats, #p < 0.05
compared to MSG rats.
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
557
Fig. 3. Minocycline protective effects are attributed to the downregulation of HMGB1/RAGE/NLRP3 inflammasome signaling and pyroptosis. A-B Protein presences of HMGB1 and
NLRP3 in oligodendrocytes of the hippocampus (n ¼ 4). C-G Representative blot (upper panel) and quantitive analyses (lower panel) of protein expression of HMGB1 (C), RAGE (D),
NLRP3 (E), ASC (F) pro-caspase-1 (G). n ¼ 4. H Protein presence of GSDMD in the oligodendrocyte of the hippocampus, (n ¼ 4). I-M Representative blot (upper panel) and quantitive
analyses (lower panel) of protein expression of caspase-1 (I), IL-1b (J), IL-18 (K), GSDMD (L), and Olig2 (M). n ¼ 4. All data are expressed as means ± SD, *p < 0.05, compared to saline
rats, #p < 0.05, compared to MSG rats.
558
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
Fig. 4. VX-765 downregulates pyroptosis in the hippocampus. A The representative tracing of rats in the open field test. B Center time spent in the open field test (n ¼ 6). C Latency
time spent in the open field test (n ¼ 6). D Center distance traveled in the open field test (n ¼ 6). E Total distance traveled in the open field test (n ¼ 6). F Sucrose consumption in the
sucrose preference test (n ¼ 6). G Immobility time spent in the forced swimming test (n ¼ 6). H-M Representative blot (upper panel) and quantitive analyses (lower panel) of protein
expression of HMGB1 (H), RAGE (I), caspase-1 (J), GSDMD (K), IL-1b (L) and IL-18 (M) n ¼ 4. All data are expressed as means ± SD, *p < 0.05, compared to saline rats, #p < 0.05,
compared to MSG rats.
downstream NLRP3 signalings, supporting the anti-inflammatory
effects of minocycline in depressive disorder. Of note, minocycline
treatment also decreased GSDMD-mediated pyroptosis in the hippocampus of depressive rats, suggesting that NLRP3 inflammasome
signals probably regulate the process of pyropotosis [25].
Pyroptosis is a newly identified form of programmed cell death.
The involvement of pyroptosis is reported in glia in the progress of
multiple sclerosis, endothelial cells in the process of atherosclerosis, and hippocampal neuron in aging-induced cognitive
dysfunction [16,26,27]. In the present study, the upregulation of
GSDMD-mediated pyroptosis proteins in the MSG-induced
depressive rats, suggesting the activation of pyroptosis in the process of depression. The involvement of pyroptosis in the development of depression was supported by VX-765 treatment since VX765 significantly downregulated GSDMD and caspase-1 expressions and reduced cytokine levels in the hippocampus. Nevertheless, the inhibitory effects of VX-765 were not observed on HMGB1/
RAGE signals, supporting the note that of GSDMD-mediated
pyroptosis was a downstream event of inflammasome signaling
[25].
The critical role of oligodendrocytes in the present study was
supported by the upregulation of Olig2 protein as well as its colocalization with both inflammasome and GSDMD-mediated
pyroptosis proteins. The role of oligodendrocytes in neuropsychiatric disorders is controversial [28,29]. Oligodendrocyte gene expressions are downregulated in stress-related neuropsychiatric
disorder [28]. However, mice depleting the oligodendrocytespecific gene 20 -30 -cyclic nucleotide 30 -phosphodiesterase are
resistant to corticosterone-stimulated depression [29]. In the present study, the activation of oligodendrocyte implies a different
source of inflammation in the central nervous system.
Of importance, the protective effects of minocycline were
observed in oligodendrocyte in the DG region, supporting the note
that impaired neurogenesis in the DG region is strongly associated
with major depressive disorder [30,31]. Thus, it is reasonable to
assume that in response to glutamine, activated oligodendrocytes
escalate local inflammation by increases in inflammasome and
pyroptosis signaling, and affect neighbor neurons.
In summary, MSG exposure activates HMGB1/RAGE/NLRP3 signalings, induces GSDMD-dependent pyroptosis in oligodendrocytes, leading to depressive disorder in SD rats. The activation of the
inflammasome and pyroptosis implies potential targets for
depression treatment.
Financial supports
The work was supported by the National Natural Science
Foundation of China (Grant No. 81673823), Natural Science Foundation of Shanghai (Grant No. 19ZR1409900), and Development
Project of Shanghai Peak Disciplines-Integrative Medicine (No.
20180101).
Transparency document
Transparency document related to this article can be found
online at https://doi.org/10.1016/j.bbrc.2020.02.149.
References
[1] G.S. Malhi, J.J. Mann, Depression, Lancet 392 (2018) 2299e2312, https://
doi.org/10.1016/s0140-6736(18)31948-2.
[2] V. Patel, D. Chisholm, R. Parikh, F.J. Charlson, L. Degenhardt, T. Dua, A.J. Ferrari,
S. Hyman, R. Laxminarayan, C. Levin, C. Lund, M.E. Medina Mora, I. Petersen,
J. Scott, R. Shidhaye, L. Vijayakumar, G. Thornicroft, H. Whiteford, Addressing
the burden of mental, neurological, and substance use disorders: key messages from Disease Control Priorities, Lancet 387 (2016) 1672e1685, https://
doi.org/10.1016/s0140-6736(15)00390-6, third ed.
[3] H. Herrman, C. Kieling, P. McGorry, R. Horton, J. Sargent, V. Patel, Reducing the
global burden of depression: a lancet-world psychiatric association commission, Lancet (2018), https://doi.org/10.1016/S0140-6736(18)32408-5.
[4] A.H. Miller, C.L. Raison, The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nat. Rev. Immunol. 16 (2016)
22e34, https://doi.org/10.1038/nri.2015.5.
[5] S.W. Lee, S. Gajavelli, M.S. Spurlock, C. Andreoni, J.P. de Rivero Vaccari,
M.R. Bullock, R.W. Keane, W.D. Dietrich, Microglial inflammasome activation
in penetrating ballistic-like brain injury, J. Neurotrauma 35 (2018)
F. Yang et al. / Biochemical and Biophysical Research Communications 526 (2020) 553e559
1681e1693, https://doi.org/10.1089/neu.2017.5530.
[6] S.R. Kim, H.J. Park, K.B. Lee, H.J. Kim, J.S. Jeong, S.H. Cho, Y.C. Lee, Epithelial
PI3K-delta promotes house dust mite-induced allergic asthma in NLRP3
inflammasome-dependent and -independent manners, Allergy Asthma
Immunol Res 12 (2020) 338e358, https://doi.org/10.4168/aair.2020.12.2.338.
[7] X.X. Li, S.K. Ling, M.Y. Hu, Y. Ma, Y. Li, P.L. Huang, Protective effects of acarbose
against vascular endothelial dysfunction through inhibiting Nox4/NLRP3
inflammasome pathway in diabetic rats, Free Radic. Biol. Med. 145 (2019)
175e186, https://doi.org/10.1016/j.freeradbiomed.2019.09.015.
[8] T.C. Franklin, E.S. Wohleb, Y. Zhang, M. Fogaca, B. Hare, R.S. Duman, Persistent
increase in microglial RAGE contributes to chronic stress-induced priming of
depressive-like behavior, Biol. Psychiatr. 83 (2018) 50e60, https://doi.org/
10.1016/j.biopsych.2017.06.034.
[9] M.G. Frank, M.D. Weber, L.R. Watkins, S.F. Maier, Stress sounds the alarmin:
the role of the danger-associated molecular pattern HMGB1 in stress-induced
neuroinflammatory priming, Brain Behav. Immun. 48 (2015) 1e7, https://
doi.org/10.1016/j.bbi.2015.03.010.
[10] M. Fleshner, M. Frank, S.F. Maier, Danger signals and inflammasomes: stressevoked sterile inflammation in mood disorders, Neuropsychopharmacology
42 (2017) 36e45, https://doi.org/10.1038/npp.2016.125, official publication of
the American College of Neuropsychopharmacology.
[11] J.M. Platnich, H. Chung, A. Lau, C.F. Sandall, A. Bondzi-Simpson, H.M. Chen,
T. Komada, A.C. Trotman-Grant, J.R. Brandelli, J. Chun, P.L. Beck, D.J. Philpott,
S.E. Girardin, M. Ho, R.P. Johnson, J.A. MacDonald, G.D. Armstrong,
D.A. Muruve, Shiga toxin/lipopolysaccharide activates caspase-4 and gasdermin D to trigger mitochondrial reactive oxygen species upstream of the
NLRP3 inflammasome, Cell Rep. 25 (2018) 1525e1536, https://doi.org/
10.1016/j.celrep.2018.09.071, e1527.
[12] N. Miao, F. Yin, H. Xie, Y. Wang, Y. Xu, Y. Shen, D. Xu, J. Yin, B. Wang, Z. Zhou,
Q. Cheng, P. Chen, H. Xue, L. Zhou, J. Liu, X. Wang, W. Zhang, L. Lu, The
cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell
pyroptosis and urinary IL-18 excretion in acute kidney injury, Kidney Int. 96
(2019) 1105e1120, https://doi.org/10.1016/j.kint.2019.04.035.
[13] B. Yuan, X.M. Zhou, Z.Q. You, W.D. Xu, J.M. Fan, S.J. Chen, Y.L. Han, Q. Wu,
X. Zhang, Inhibition of AIM2 inflammasome activation alleviates GSDMDinduced pyroptosis in early brain injury after subarachnoid haemorrhage,
Cell Death Dis. 11 (2020) 76, https://doi.org/10.1038/s41419-020-2248-z.
[14] X.Y. Wu, K.T. Li, H.X. Yang, B. Yang, X. Lu, L.D. Zhao, Y.Y. Fei, H. Chen, L. Wang,
J. Li, L.Y. Peng, W.J. Zheng, Y. Hou, Y. Jiang, Q. Shi, W. Zhang, F.C. Zhang,
J.M. Zhang, B. Huang, W. He, X. Zhang, Complement C1q synergizes with PTX3
in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis, J. Autoimmun. 106 (2020), 102336, https://doi.org/10.1016/
j.jaut.2019.102336.
[15] Y.L. Wang, Q.Q. Han, W.Q. Gong, D.H. Pan, L.Z. Wang, W. Hu, M. Yang, B. Li,
J. Yu, Q. Liu, Microglial activation mediates chronic mild stress-induced
depressive- and anxiety-like behavior in adult rats, J. Neuroinflammation 15
(2018) 21, https://doi.org/10.1186/s12974-018-1054-3.
[16] B.A. McKenzie, M.K. Mamik, L.B. Saito, R. Boghozian, M.C. Monaco, E.O. Major,
J.Q. Lu, W.G. Branton, C. Power, Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis, Proc. Natl.
Acad. Sci. U. S. A. 115 (2018) E6065eE6074, https://doi.org/10.1073/
pnas.1722041115.
[17] D. Wu, R. Han, S. Deng, T. Liu, T. Zhang, H. Xie, Y. Xu, Protective effects of
flagellin A N/C against radiation-induced NLR pyrin domain containing 3
inflammasome-dependent pyroptosis in intestinal cells, Int. J. Radiat. Oncol.
Biol. Phys. 101 (2018) 107e117, https://doi.org/10.1016/j.ijrobp.2018.01.035.
[18] C.B. Quines, S.G. Rosa, D. Velasquez, J.T. Da Rocha, J.S. Neto, C.W. Nogueira,
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
559
Diphenyl diselenide elicits antidepressant-like activity in rats exposed to
monosodium glutamate: a contribution of serotonin uptake and Na(þ), K(þ)ATPase activity, Behav. Brain Res. 301 (2016) 161e167, https://doi.org/
10.1016/j.bbr.2015.12.038.
Y. Xu, H. Sheng, Q. Bao, Y. Wang, J. Lu, X. Ni, NLRP3 inflammasome activation
mediates estrogen deficiency-induced depression- and anxiety-like behavior
and hippocampal inflammation in mice, Brain Behav. Immun. 56 (2016)
175e186, https://doi.org/10.1016/j.bbi.2016.02.022.
F.M. Noe, N. Polascheck, F. Frigerio, M. Bankstahl, T. Ravizza, S. Marchini,
L. Beltrame, C.R. Bandero, W. Loscher, A. Vezzani, Pharmacological blockade of
IL-1beta/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy, Neurobiol. Dis. 59
(2013) 183e193, https://doi.org/10.1016/j.nbd.2013.07.015.
C.B. Quines, S.G. Rosa, J.T. Da Rocha, B.M. Gai, C.F. Bortolatto, M.M. Duarte,
C.W. Nogueira, Monosodium glutamate, a food additive, induces depressivelike and anxiogenic-like behaviors in young rats, Life Sci. 107 (2014) 27e31,
https://doi.org/10.1016/j.lfs.2014.04.032.
A. Martinez-Contreras, M. Huerta, S. Lopez-Perez, J. Garcia-Estrada, S. Luquin,
C. Beas Zarate, Astrocytic and microglia cells reactivity induced by neonatal
administration of glutamate in cerebral cortex of the adult rats, J. Neurosci.
Res. 67 (2002) 200e210, https://doi.org/10.1002/jnr.10093.
F.N. Kaufmann, A.P. Costa, G. Ghisleni, A.P. Diaz, A.L.S. Rodrigues, H. Peluffo,
M.P. Kaster, NLRP3 inflammasome-driven pathways in depression: clinical
and preclinical findings, Brain Behav. Immun. 64 (2017) 367e383, https://
doi.org/10.1016/j.bbi.2017.03.002.
M. Iwata, K.T. Ota, X.Y. Li, F. Sakaue, N. Li, S. Dutheil, M. Banasr, V. Duric,
T. Yamanashi, K. Kaneko, K. Rasmussen, A. Glasebrook, A. Koester, D. Song,
K.A. Jones, S. Zorn, G. Smagin, R.S. Duman, Psychological stress activates the
inflammasome via release of adenosine triphosphate and stimulation of the
purinergic type 2X7 receptor, Biol. Psychiatr. 80 (2016) 12e22, https://
doi.org/10.1016/j.biopsych.2015.11.026.
B.A. McKenzie, V.M. Dixit, C. Power, Fiery cell death: pyroptosis in the central
nervous system, Trends Neurosci. 43 (2020) 55e73, https://doi.org/10.1016/
j.tins.2019.11.005.
X. Wu, H. Zhang, W. Qi, Y. Zhang, J. Li, Z. Li, Y. Lin, X. Bai, X. Liu, X. Chen,
H. Yang, C. Xu, Y. Zhang, B. Yang, Nicotine promotes atherosclerosis via ROSNLRP3-mediated endothelial cell pyroptosis, Cell Death Dis. 9 (2018) 171,
https://doi.org/10.1038/s41419-017-0257-3.
Y. Fan, L. Du, Q. Fu, Z. Zhou, J. Zhang, G. Li, J. Wu, Inhibiting the NLRP3
inflammasome with MCC950 ameliorates isoflurane-induced pyroptosis and
cognitive impairment in aged mice, Front. Cell. Neurosci. 12 (2018) 426,
https://doi.org/10.3389/fncel.2018.00426.
F. Cathomas, D. Azzinnari, G. Bergamini, H. Sigrist, M. Buerge, V. Hoop,
B. Wicki, L. Goetze, S. Soares, D. Kukelova, E. Seifritz, S. Goebbels, K.A. Nave,
M.S. Ghandour, C. Seoighe, T. Hildebrandt, G. Leparc, H. Klein, E. Stupka,
B. Hengerer, C.R. Pryce, Oligodendrocyte gene expression is reduced by and
influences effects of chronic social stress in mice, Gene Brain Behav. 18 (2019),
e12475, https://doi.org/10.1111/gbb.12475.
N.M. Edgar, C. Touma, R. Palme, E. Sibille, Resilient emotionality and molecular
compensation in mice lacking the oligodendrocyte-specific gene Cnp1, Transl.
Psychiatry 1 (2011) e42, https://doi.org/10.1038/tp.2011.40.
Y. Hayashi, H. Jinnou, K. Sawamoto, S. Hitoshi, Adult neurogenesis and its role
in brain injury and psychiatric diseases, J. Neurochem. 147 (2018) 584e594,
https://doi.org/10.1111/jnc.14557.
S. Hitoshi, N. Maruta, M. Higashi, A. Kumar, N. Kato, K. Ikenaka, Antidepressant
drugs reverse the loss of adult neural stem cells following chronic stress,
J. Neurosci. Res. 85 (2007) 3574e3585, https://doi.org/10.1002/jnr.21455.