Progesterone and the Spinal Cord: Good Friends in Bad Times

Abstract

In recent years, a growing list of publications point to the value of steroid hormones as an interesting option for the treatment of several type of lesions and diseases of the nervous system. Progesterone, well known for its role in pregnancy, has recently been shown to exert neuroprotective and promyelinating effects in both, the peripheral and central nervous system, including the injured spinal cord. Previous work from our laboratory has shown that progesterone actions in experimental models of spinal neurodegeneration or injury may involve the modulation of brain-derived neurotrophic factor, a neurotrophin with important implications in neuronal survival and axonal regeneration. The spinal cord is target for progesterone since neurons and glial cells express the intracellular receptors for this neuroactive steroid. However, the presence in the spinal cord of new membrane receptors and the enzymes involved in progesterone metabolism to its reduced derivatives, which modulate the activity of neurotransmitter receptors, suggest that progesterone actions involve pleiotropic mechanisms. Our recent data uncovering several molecular events may help to understand the protective and promyelinating actions of progesterone and further support the role of this steroid as a promising therapeutic agent for neurotrauma and/or neurodegenerative diseases.

Progesterone Receptor-B Induction of BIRC3 Protects Endometrial Cancer Cells from AP1-59-Mediated Apoptosis

“…It should be noted that the common trend in these studies is that long-term treatment or supraphysiological concentrations of the hormone is required to see an effect in cell growth and apoptosis which makes it challenging to pinpoint specific mechanisms of PR that are associated with these effects. On the other hand, studies have demonstrated a protective effect of progesterone against neuronal cerebral damage [34, 35], in cardiomyocytes treated with doxorubicin [36], spinal cord injury [37, 38], and radiation-induced apoptosis in breast cancer cells [39]. In our study, knockdown of PR in PRB-specific Ishikawa cells for 72 h promoted apoptosis whether ligand was present or not, while knockdown of PR in PRA-specific cells did not significantly affect apoptosis.…”

Neuroprotective Actions of Neurosteroids

“…The hormone administered for 3 days following the spinal cord injury improved myelination, increased the level of brain derived neurotrophic factor (BDNF) mRNA and reduced chromatolysis (De Nicola et al, 2006), whereas 5-day administration diminished the size of lesions and prevented secondary neuronal loss (Thomas et al, 1999). According to Labombarda et al (2010) PROG significantly enhanced BDNF neuronal expression, up-regulated growth-associated protein 43 (GAP-43) necessary for axonal regeneration, prevented the injury-induced chromatolytic changes of spinal neurons and increased activity of enzymes crucial for normal neuronal metabolism and neurotransmission, and restored impaired expression of the Na,K-ATPase subunits and choline acetyltransferase. On the other hand, Coughlan et al (2009) found no evidence for neuroprotective relationship between BDNF and PROG.…”

“…Administration of PROG following acute spinal cord injury in rats attenuated the loss of microtubule-associated protein 2, a major component of the cytoskeleton (González et al, 2009). In addition, this steroid acts as a promyelinating factor by stimulating synthesis of myelin proteins and proliferation/differentiation of oligodendrocyte progenitors (Gonzalez et al, 2005; Labombarda et al, 2010). …”

Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury

“…Its actions in the central nervous system are not limited to the control of neuroendocrine regulation and reproduction (Baulieu and Schumacher, 2000, Birzniece, et al, 2006); it influences several neural survival functions including neuronal and glial differentiation, hippocampal neurogenesis, and synaptic stability (Ghoumari, et al, 2005, Smith, et al, 1987, Tsutsui, et al, 2004, Zhang, et al, 2010). There are now more than 160 publications showing that progesterone is an effective neuroprotective agent against a number of different insults including blunt and penetrating traumatic brain injury (TBI) (De Nicola, et al, 2009, Garcia-Estrada, et al, 1999, Labombarda, et al, 2010, Schumacher, et al, 2007, Stein, 2007, Stein and Sayeed, 2010, Stein and Wright, 2010), diffuse TBI (O’Connor, et al, 2007), stroke (Ishrat, et al, 2010, Sayeed and Stein, 2009), anoxic brain injury, glutamate toxicity (Ogata, et al, 1993), and spinal cord injury (Labombarda, et al, 2010) in both males and females. Progesterone exerts its beneficial effects in the central nervous system via multiple pathways that are not always dependent on the activation of the classical intranuclear progesterone receptor (Bottino, et al, 2010, Falkenstein, et al, 2000, Losel, et al, 2003).…”