The role of the neuroinflammation and stressors in premenstrual syndrome/premenstrual dysphoric disorder: a review

Abstract

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are prevalent emotional disorders in females, characterized by cyclic variations in physiological stress responses and emotional symptoms that correspond with the menstrual cycle. Despite extensive research, the underlying causes of these disorders remain elusive. This review delves into the neurobiological mechanisms connecting stress-induced neuroinflammation with PMS/PMDD. Additionally, it traces the conceptual development and historical context of PMS/PMDD. The review further evaluates clinical evidence on the association between PMS/PMDD and stress, along with findings from both clinical and animal studies that link these disorders to inflammatory processes. Additionally, the neurobiological pathways by which inflammatory responses may play a role in the pathogenesis of PMS/PMDD were elucidated, including their interactions with the hypothalamic-pituitary-ovary (HPO) axis, serotonin-kynurenine (5-HT-KYN) system, GABAergic system, brain-derived neurotrophic factor (BDNF), hypothalamic-pituitary-adrena(HPA)axis and. Future research is encouraged to further investigate the pathogenesis of PMS/PMDD through the perspective of neuroinflammatory responses.

Keywords: blood-brain barrier; kynurenine; neuroinflammation; premenstrual dysphoric disorder; premenstrual syndrome; stress.

Figure 1

Mechanisms of peripheral inflammation transitioning to central inflammation (59). This process can be categorized into five critical aspects according to existing literature; (1) Alterations in tight junction; (2) Damage to cerebral vascular endothelial cells; (3) Activation of microglia and astrocytes; (4) Infiltration of peripheral immune cells; (5) Changes in various transport pathways and receptors. P-gp, P-glycoprotein (or P-glycoprotein 1); MMPs, matrix Metalloproteinases; LPS, lipopolysaccharide; IL-1β, interleukin-1 Beta; IL-6, interleukin-6; IL-17, interleukin-17; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; CCL2, chemokine (C-C motif) ligand 2; CD4+T cells, CD4 T cell-mediated immunity; γδ T-cell, δ T Lymphocytes; CD8+T cells, Cytotoxic T lymphocytes; B cell, B lymphocytes; NK cell, natural killer cell.

Figure 2

Potential mechanisms of PMS/PMDD pathogenesis involving 5-HT-KYN and inflammatory responses. The removal of tryptophan, the precursor of serotonin, from the diet induces premenstrual symptoms (86). TRY metabolism bifurcates into two distinct pathways: the “excitotoxic” and “neuroprotective” branches. Dysregulation in neurotoxic (such as 3-HK and QUIN) and neuroprotective (such as KYNA) TRYCATs is a key factor in the pathophysiology of mood disorders. These pathways are intricately linked to inflammatory responses: the excitotoxic pathway (TRY—KYN—3-HK—QUIN) is primarily metabolized by microglia, whereas the neuroprotective pathway (TRY—KYN—KYNA) is predominantly processed by astrocytes (99). 5-HTP, 5-hydroxytryptophan; 5-HT, serotonin; 5-HIAA, 5-hydroxyindole acetic acid Aminomuconic semialdehyde; AA, anthranilic acid; KYNU, kynureninase; KYNA, kynurenic acid; KAT, kynurenine aminotransferase; XA, xanthurenic acid; PA, positive affect; ACMSD, amino-B-carboxymuconate-semialdehyde-decarboxylase; TRP, tryptophan; TDO, tryptophan 2,3-dioxygenase; IDO, indole 2,3-dioxygenase; NFK, N’-formyl-L-kynurenine; AFMID, Arylformamidase; KYN, kynurenine; KMO, kynurenine mono-oxygenase; 3-HK, 3-hydroxy-kynurenine; 3-HAA, 3-hydroxy-anthranilic acid; HAAO, 3-hydroxyanthranilate-3,4-dioxygenase; QUIN, quinolinic acid; QPRT, quinolinate phosphoribosyl transferase; NAD+, nicotinamide adenine dinucleotide.

Figure 3

Mechanism by which inflammatory mediators regulate GABAA_R transmission leading to PMDD pathogenesis. The increased expression of GABAA_R subunits results in diminished chloride influx, which subsequently inhibits GABA release from GABAergic interneurons, contributing to PMDD development (104). Among the GABAA_R α subunits closely associated with PMDD, polyI (a TLR3 agonist) has been shown to elevate the expression of the α2 and α3 subunit proteins while reducing the expression of the α4 and α6 subunit proteins. Additionally, the LPS receptor TLR4 enhances the expression of the GABAA_R α2 subunit. Conversely, GABAA_R activity suppresses the expression of inflammatory cytokines, including TNF-α, IL-17, IL-6, and IL-10. LPS, Lipopolysaccharide; TLR4, Toll-like receptor 4; IL-17, interleukin-17; TNF-α, tumor necrosis factor alpha; IL-10, interleukin-10; IL-6, interleukin-6; ENO1, enolase 1 Gene; NF-κB, nuclear factor kappa-B; TLR3, Toll-like receptor 3; GABAA_R α2, Gamma-aminobutyric acid type A receptor subunit alpha 2; GABAA_R α3, Gamma-aminobutyric acid type A receptor subunit alpha 3; GABAA_R α4, Gamma-aminobutyric acid type A receptor subunit alpha 4; GABAA_R α5, Gamma-aminobutyric acid type A receptor subunit alpha 5; GABAA_R α6, Gamma-aminobutyric acid type A receptor subunit alpha 6; GABAAR δ, Gamma-aminobutyric acid type A receptor subunit delta.

Figure 4

PMDD and stress-induced changes in BDNF and inflammation mechanisms. The elevated BDNF levels observed in the luteal phase of PMDD may reflect a compensatory response to chronic stress and increased inflammatory activity. LPS-induced inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-10, inhibit BDNF expression and receptor phosphorylation, thereby disrupting BDNF signaling. When BDNF binds to its receptor TrkB, it triggers receptor activation, leading to dimerization and autophosphorylation of tyrosine residues within the cytoplasmic kinase domain. Each phosphorylation event initiates distinct signaling pathways: Ras/PI3K/Akt, Ras/MEK/Erk, or PLCγ, which in turn activate transcription factors such as CREB and NF-κB. Additionally, proBDNF interacts with the P75 neurotrophin receptor (P75^NTR), initiating the IRAK/TRAF6/JNK cascade, which also activates NF-κB. NF-κB is a key regulator of cellular stress responses and inflammatory processes (147). LPS, Lipopolysaccharide; TLR4, Toll-like receptor 4; TLR3, Toll-like receptor 3; p75NTR, Neurotrophin Receptor P75; MyD88, Myeloid Differentiation Primary Response Protein 88; IRAK-4, Interleukin-1 Receptor-Associated Kinase 4; IRAK-1, Interleukin-1 Receptor-Associated Kinase 1; IRAK-2, Interleukin-1 Receptor-Associated Kinase 2; TRAF-6, TNF receptor associated factor 6; TAK-1, transforming growth factor beta-activated kinase 1; JNK, c-Jun N-terminal kinase; NEMO, NF-κB Essential Modulator; IκB, inhibitor of NF-κB; SHC, SHC transforming protein; BDNF, brain-derived neurotrophic factor; Trkb, Tropomyosin receptor kinase B; GRB2, growth factor receptor-bound protein 2; SOS, son of sevenless homolog; Ras, rat sarcoma; MEK, mitogen-activated protein; ERK1/2, extracellular-signa1regulated kinase; RSK, ribosomal S6 kinase; NF-κB, nuclear factor kappa-B; Gab1, GRB2-Associated Binding Protein 1; PI3K, Phosphoinositide 3-Kinase; AKT, protein kinase B; PLC-γ, Phospholipase C gamma 1; CREB, CAMP-response element binding protein; IP3, inositol triphosphate; Ca2+/CaM, Ca/calmodulin-dependent protein kinases; CaMKII, Calcium Calmodulin Dependent Protein Kinase II; CaMKIV, Calcium-/Calmodulin-Dependent Protein Kinase IV.