Both PROG and VDH are pleiotropic and affect multiple pathways, which may account for their therapeutic effectiveness. Here we show a few of the major pathways involved in injury and discussed in this paper, with the general scheme of blue as beneficial or protective and red as detrimental. 1. Inflammatory pathways consisting of immune cell recruitment and infiltration (macrophages; MΦ), microglial activation and inflammatory cytokine release (TNFα and IL-1), and naive T cell (T_H0) differentiation into pro-inflammatory type 1 (T_H1) and anti-inflammatory type 2 (T_H2). These processes can lead to cell death, edema, and secondary damage; 2. Maintenance of blood-brain barrier (BBB) integrity, including modulation of the expression of channels and transporters such as P-glycoprotein (Pgp) and aquaporin 4 (AQP4) and antioxidant protection for both capillary endothelium and astrocytes. Failure of BBB function is a key component in the development of edema; 3. Glutamate excitotoxicity, mediated primarily by NMDA channels, can be toxic to the cell due to Na+ influx and severe depolarization. These effects can be counteracted by Cl^- influx through GABA_A channels, leading to repolarization; 4. The balance of cellular pro- and anti-death mechanisms, including release of pro-apoptotic mitochondrial (Bax, BAD, cytochrome c) and anti-apoptotic (Bcl-2) proteins, caspase-3 activation, maintenance of ionic and energy balance, as well as reduction of Ca²⁺ influx, which is the final common pathway of most mechanisms of cell death including glutamate toxicity. Since the activation of cellular reproductive machinery in terminally differentiated neurons can also lead to apoptosis, arrest of the cell cycle can also be protective; 5. Upregulation of trophic factors, especially NGF and BDNF, which contribute not only to the maintenance of neurons and astrocytes, but also oligodendrocytes and myelination; 6. Antioxidant defenses, which reduce the damage of immune and endogenously released reactive oxygen species (ROS) to cellular components and membranes. L-VSCC: L-type voltage-sensitive Ca²⁺ channel; Na⁺,K⁺-ATPase: Na⁺/K⁺ active transport pump.

The chemical structure of progesterone.

The metabolism of vitamin D and its conversion from 7-dehydrocholesterol to vitamin D hormone (VDH). 25OHD₃: 25-hydroxyvitamin D₃; UVB: ultraviolet B solar radiation; CYP2R1: vitamin D 25-hydroxylase; 1α-OHase: 25-hydroxyvitamin D₃ 1α-hydroxylase.