Neuroprotective effects of estrogen in CNS injuries: insights from animal models

Figures & data

Figure 1 Biosynthesis of E2 from cholesterol.

Note: The intermediate products are also important steroidal sex hormones and some of them have shown notable neuroprotective actions.
Abbreviation: E2, estradiol.

Figure 2 Various molecular mechanisms of E2 for its neuroprotective effects.

Notes: Genomic and nongenomic signaling mechanisms are mostly involved in modulation of expression or activity of multiple molecular components for inhibition of apoptosis and promotion of cell survival. Its antioxidant functions are useful for scavenging reactive free radicals, which are heavily produced following a CNS injury. Moreover, E2 plays an important role in maintaining mitochondrial bioenergetics for the optimal production of ATP for supporting cellular metabolism.
Abbreviations: ATP, adenosine triphosphate; CNS, central nervous system; E2, estradiol; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase.

Table 1 The three main E2 receptors, their CNS locations, and their effects upon ligand binding

Receptor	Location	Effects upon activation
ERα	CNS	Decreases inflammation, decreases the extent of lesion, and prevents mitochondrial damage and release of cytochrome c, thus inhibiting apoptosis
ERβ	Abundant in supraoptic nucleus of hypothalamus and other areas of CNS	Decreases the extent of tissue damage and regulates the expression of genes in neurons that encode for vasopressin, oxytocin, and other hypothalamic hormones
GPER1/GPR30	Gray and white matter of the spinal cord	Protects against free radicals and provides antioxidant effects

Abbreviations: CNS, central nervous system; E2, estradiol; ER, estrogen receptor; GPER1/GPR30, G protein-coupled estrogen receptor 1 / G protein-coupled receptor 30 .

Figure 3 E2 has genomic signaling mechanisms for modulation of expression of various proteins for its neuroprotective effects in the CNS.

Notes: Activation ERs by E2 modulates the expression of the target genes, so as to decrease the detrimental pathways, thus leading to neuroprotection.
Abbreviations: CNS, central nervous system; E2, estradiol; ERs, estrogen receptors; MMP-9, matrix metalloprotease-9; TNF-α, tumor necrosis factor-alpha.

Table 2 Effects of MP, the current drug used for SCI treatment, and E2 in the spinal cord

Therapeutic agent	Protective and side effects in the spinal cord
	Cervical cord infarction Flaccid quadriplegia Aseptic meningitis Arachnoiditis Preservation of glial cells, but failure of functionality in the spinal cord
	Reduction of inflammation Preservation of tissue Improvement in locomotor function Promotion of CNS development Induction of antiapoptotic effects

Abbreviations: CNS, central nervous system; E2, estradiol; MP, methylprednisolone; SCI, spinal cord injury.

Figure 4 Chemical structures of the main component in Premarin and of 2ME2 and their therapeutic effects.

Notes: Both Premarin and 2ME2 provide significant amounts of neuroprotection. In addition to its neuroprotective effects, 2ME2 has other beneficial effects in the body. The different color boxes were used to indicate different beneficial effects of 2ME2.
Abbreviation: 2ME2, 2-methoxyestradiol.

Figure 5 E2 activates both protective and reparative mechanisms in CNS injuries in vivo.

Note: Different color fonts and arrows indicate diverse biological activities of E2.
Abbreviations: CNS, central nervous system; E2, estradiol.

Figure 6 Boron-containing E2 molecules may be more effective than E2 for neuroprotection.

Abbreviation: E2, estradiol.