Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors View Full Text


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Article Info

DATE

2021-10-18

AUTHORS

Radwa N. Muhammad, Lamiaa A. Ahmed, Rania M. Abdul Salam, Kawkab A. Ahmed, Amina S. Attia

ABSTRACT

Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood–brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium–glucose co‐transporter‐2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling.Graphical abstractGraphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood–brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com. More... »

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    24 schema:description Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood–brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium–glucose co‐transporter‐2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling.Graphical abstractGraphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood–brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com.
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    29 schema:keywords B receptor
    30 BBB
    31 BBB disruption
    32 BBB function
    33 BBB integrity
    34 BDNF
    35 BDNF/ZO-1 axis
    36 BQ-788
    37 Cortical ZO-1 expression
    38 DAPA
    39 Dapa administration
    40 ET system
    41 ET system disturbance
    42 ET-1
    43 ET-1 release
    44 ET-1/ETBR/BDNF/ZO-1 axis
    45 ETBR Signaling
    46 ETBR blocker
    47 ETBR expression
    48 ETBR gene expression
    49 ETBR signal transduction
    50 ETBR/BDNF/ZO-1 axis
    51 EtBr
    52 Graphical abstractGraphical illustration
    53 IL
    54 NF-κB
    55 NLRP3
    56 NLRP3 inflammasome activation
    57 NLRP3 inflammasome pathway
    58 NLRP3/ET-1/ETBR/BDNF/ZO-1 axis
    59 NLRP3/TNF
    60 SGLT2 inhibitors
    61 TNF
    62 Wistar rats
    63 ZO-1 axis
    64 ZO-1 expression
    65 abstractGraphical illustration
    66 action
    67 activation
    68 active NLRP3
    69 administration
    70 adolescent male Wistar rats
    71 animal models
    72 animals
    73 anti-depressant potential
    74 antidepressant action
    75 antidepressant potential
    76 assembly
    77 attenuation
    78 available standard therapies
    79 axis
    80 barrier integrity
    81 barriers
    82 behavior
    83 behavioral variables
    84 blockers
    85 blood-brain barrier
    86 blood-brain barrier integrity
    87 cell activation
    88 central inflammatory response
    89 central nervous system
    90 chronic unpredictable stress protocol
    91 concern
    92 cornerstone
    93 cornerstone outcome
    94 co‐transporter‐2 inhibitor
    95 damage
    96 dapagliflozin
    97 depression
    98 depression-like behavior
    99 depressive animals
    100 disruption
    101 disturbances
    102 domain
    103 domain-containing protein 3
    104 effect
    105 endothelin B receptor
    106 endothelin-1
    107 enhanced production
    108 expression
    109 factor kappa B
    110 factors
    111 function
    112 further damage
    113 gene expression
    114 glial cell activation
    115 health concern
    116 hippocampal BDNF
    117 illustration
    118 impact
    119 indirect effects
    120 inflammasome activation
    121 inflammasome pathway
    122 inflammatory response
    123 influence
    124 inhibition
    125 inhibitors
    126 integrity
    127 interleukin
    128 kappa B
    129 leucine-rich repeats
    130 major role
    131 male Wistar rats
    132 manipulation
    133 marked activation
    134 mechanism
    135 miR-501-3p signaling
    136 miRNAs
    137 model
    138 modulation
    139 modulatory role
    140 necrosis factor
    141 nervous system
    142 neuro-inflammation
    143 neuroplasticity
    144 neurotrophin production
    145 neurotrophins
    146 noticeable reduction
    147 nuclear factor kappa B
    148 observations
    149 oligomerization domain
    150 outcomes
    151 overall state
    152 overwhelming health concern
    153 pathological pathways
    154 pathway
    155 patients
    156 positive outcomes
    157 potential
    158 pro-inflammatory IL
    159 production
    160 prominent reduction
    161 promising
    162 protein 3
    163 protocol
    164 pyrin domain-containing protein 3
    165 rats
    166 receptors
    167 reduction
    168 regulation
    169 release
    170 repeats
    171 resilience
    172 resilience mechanisms
    173 response
    174 results
    175 role
    176 role of ETBR
    177 signal transduction
    178 signaling
    179 significant role
    180 sodium-glucose co-transporter-2 inhibitors
    181 specific ETBR blocker
    182 standard therapy
    183 state
    184 stress
    185 stress protocol
    186 subsequent inhibition
    187 synapsin 1
    188 system
    189 system disturbances
    190 therapy
    191 transduction
    192 tumor necrosis factor
    193 unpredictable stress protocol
    194 variables
    195 schema:name Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors
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