The phytoestrogen genistein improves hippocampal neurogenesis and cognitive impairment and decreases neuroinflammation in an animal model of metabolic syndrome.

Metabolic syndrome (MS) is the medical term for the combination of at least three of the following factors: obesity, hyperlipidemia, hyperglycemia, insulin resistance, and hypertension. The spontaneously hypertensive rat (SHR) is an accepted animal model for the study of human MS that reveals all the features of the syndrome when fed high-fat, high-carbohydrate diets. The intake of high-fat diets in rats has been shown to produce brain neuropathology.

Instrumental successive negative contrast in rats: Trial distribution, reward magnitude, and prefrontal cortex activation.

Successive negative contrast (SNC) has been used to study reward relativity, reward loss, and frustration for decades. In instrumental SNC (iSNC), the anticipatory performance of animals downshifted from a large reward to a small reward is compared to that of animals always reinforced with the small reward. iSNC involves a transient deterioration of anticipatory behavior in downshifted animals compared to unshifted controls.

Beneficial effects of the phytoestrogen genistein on hippocampal impairments of spontaneously hypertensive rats (SHR).

Hippocampal neuropathology is a recognized feature of the spontaneously hypertensive rat (SHR). The hippocampal alterations associate with cognitive impairment. We have shown that hippocampal abnormalities are reversed by 17β-estradiol, a steroid binding to intracellular receptors (estrogen receptor α and β subtypes) or the membrane-located G-protein coupled estradiol receptor.

Brain and spinal cord trauma: what we know about the therapeutic potential of insulin growth factor 1 gene therapy.

Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal cord injury, several reports have described impairments in cognitive abilities. Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal cord injury. These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes, drugs of abuse, and combined medication.

IGF1 Gene Therapy Reversed Cognitive Deficits and Restored Hippocampal Alterations After Chronic Spinal Cord Injury.

The hippocampus is implicated in the generation of memory and learning, processes which involve extensive neuroplasticity. The generation of hippocampal adult-born neurons is particularly regulated by glial cells of the neurogenic niche and the surrounding microenvironment. Interestingly, recent evidence has shown that spinal cord injury (SCI) in rodents leads to hippocampal neuroinflammation, neurogenesis reduction, and cognitive impairments.

Combination of Defined CatWalk Gait Parameters for Predictive Locomotion Recovery in Experimental Spinal Cord Injury Rat Models.

In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB) score. In comparison, CatWalk is an automated gait analysis system, providing further parameter specifications.

Spinal Cord Injury Leads to Hippocampal Glial Alterations and Neural Stem Cell Inactivation.

The hippocampus encodes spatial and contextual information involved in memory and learning. The incorporation of new neurons into hippocampal networks increases neuroplasticity and enhances hippocampal-dependent learning performances. Only few studies have described hippocampal abnormalities after spinal cord injury (SCI) although cognitive deficits related to hippocampal function have been reported in rodents and even humans.

Activation of the G Protein-Coupled Estrogen Receptor (GPER) Increases Neurogenesis and Ameliorates Neuroinflammation in the Hippocampus of Male Spontaneously Hypertensive Rats.

It is known that spontaneously hypertensive rats (SHR) present a marked encephalopathy, targeting vulnerable regions such as the hippocampus. Abnormalities of the hippocampus of SHR include decreased neurogenesis in the dentate gyrus (DG), partial loss of neurons in the hilus of the DG, micro and astrogliosis and inflammation. It is also known that 17β-estradiol (E2) exert neuroprotective effects and prevent hippocampal abnormalities of SHR.

Progesterone receptor-mediated actions and the treatment of central nervous system disorders: An up-date of the known and the challenge of the unknown.

Progesterone has been shown to exert a wide range of remarkable protective actions in experimental models of central nervous system injury or disease. However, the intimate mechanisms involved in each of these beneficial effects are not fully depicted. In this review, we intend to give the readers a thorough revision on what is known about the participation of diverse receptors and signaling pathways in progesterone-mediated neuroprotective, pro-myelinating and anti-inflammatory outcomes, as well as point out to novel regulatory mechanisms that could open new perspectives in steroid-based therapies.

Progesterone effects on the oligodendrocyte linage: all roads lead to the progesterone receptor.

A new role has emerged for progesterone after discovering its potent actions away from reproduction in both the central and the peripheral nervous system. The aim of the present report is to discuss progesterone's mechanisms of action involved in myelination, remyelination and neuroinflammation. The pivotal role of the classic progesterone receptor is described and evidence is compiled about progesterone's direct effects on oligodendrocyte linage and its indirect effects on oligodendrocyte precursor cell differentiation by decreasing the neuroinflammatory environment.

Spinal cord injury drives chronic brain changes.

Only a few studies have considered changes in brain structures other than sensory and motor cortex after spinal cord injury, although cognitive impairments have been reported in these patients. Spinal cord injury results in chronic brain neuroinflammation with consequent neurodegeneration and cognitive decline in rodents. Regarding the hippocampus, neurogenesis is reduced and reactive gliosis increased.

Spinal Cord Injury Impairs Neurogenesis and Induces Glial Reactivity in the Hippocampus.

The incorporation of newborn neurons with increased synaptic remodeling and activity-dependent plasticity in the dentate gyrus enhances hippocampal-dependent learning performances. Astrocytes and microglial cells are components of the neurogenic niche and regulate neurogenesis under normal and neurophatological conditions leading to functional consequences for learning and memory. Although cognitive impairments were reported in patients after spinal cord injury (SCI), only few studies have considered remote changes in brain structures which are not related with sensory and motor cortex.

Temporal changes in the expression of the translocator protein TSPO and the steroidogenic enzyme 5α-reductase in the dorsal spinal cord of animals with neuropathic pain: Effects of progesterone administration.

Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. The presence and biological activity of steroidogenic regulatory proteins and enzymes in the spinal cord suggests that neurosteroids locally generated could modulate pain messages. In this study we explored temporal changes in the spinal expression of the 18kDa translocator protein TSPO, the steroidogenic acute regulatory protein (StAr) and the steroidogenic enzyme 5α-reductase (5α-RI/II) in an experimental model of central chronic pain.

Neuroactive steroids, nociception and neuropathic pain: A flashback to go forward.

The present review discusses the potential role of neurosteroids/neuroactive steroids in the regulation of nociceptive and neuropathic pain, and recapitulates the current knowledge on the main mechanisms involved in the reduction of pain, especially those occurring at the dorsal horn of the spinal cord, a crucial site for nociceptive processing. We will make special focus on progesterone and its derivative allopregnanolone, which have been shown to exert remarkable actions in order to prevent or reverse the maladaptive changes and pain behaviors that arise after nervous system damage in various experimental neuropathic conditions.

Progesterone modulates pro-inflammatory cytokine expression profile after spinal cord injury: Implications for neuropathic pain.

Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1β, its receptors (IL-1RI and IL-1RII) and antagonist (IL-1ra), IL-6 and TNFα, and NR1 subunit of NMDAR.

A functional progesterone receptor is required for immunomodulation, reduction of reactive gliosis and survival of oligodendrocyte precursors in the injured spinal cord.

The anti-inflammatory effects of progesterone have been increasingly recognized in several neuropathological models, including spinal cord inflammation. In the present investigation, we explored the regulation of proinflammatory factors and enzymes by progesterone at several time points after spinal cord injury (SCI) in male rats. We also demonstrated the role of the progesterone receptor (PR) in inhibiting inflammation and reactive gliosis, and in enhancing the survival of oligodendrocyte progenitors cells (OPC) in injured PR knockout (PRKO) mice receiving progesterone.

Analytical challenges for measuring steroid responses to stress, neurodegeneration and injury in the central nervous system.

Levels of steroids in the adult central nervous system (CNS) show marked changes in response to stress, degenerative disorders and injury. However, their analysis in complex matrices such as fatty brain and spinal cord tissues, and even in plasma, requires accurate and precise analytical methods. Radioimmunoassays (RIA) and enzyme-linked immunosorbent assays, even with prepurification steps, do not provide sufficient specificity, and they are at the origin of many inconsistent results in the literature.

Give progesterone a chance.

There is currently no standard pharmacological treatment for spinal cord injury. Here, we suggest that progesterone, a steroid hormone, may be a promising therapeutical candidate as it is already for traumatic brain injury, where it has reached phase II clinical trials. We rely on previous works showing anti-inflammatory, neuroprotective and promyelinating roles for progesterone after spinal cord injury and in our recent paper, in which we demonstrate that progesterone diminishes lesion, preserves white matter integrity and improves locomotor recovery in a clinically relevant model of spinal cord lesion.

Progesterone reduces secondary damage, preserves white matter, and improves locomotor outcome after spinal cord contusion.

Progesterone is an anti-inflammatory and promyelinating agent after spinal cord injury, but its effectiveness on functional recovery is still controversial. In the current study, we tested the effects of chronic progesterone administration on tissue preservation and functional recovery in a clinically relevant model of spinal cord lesion (thoracic contusion). Using magnetic resonance imaging, we observed that progesterone reduced both volume and rostrocaudal extension of the lesion at 60 days post-injury.

Therapeutic effects of progesterone in animal models of neurological disorders.

Substantial evidence supports that progesterone exerts many functions in the central and peripheral nervous system unrelated to its classical role in reproduction. In this review we first discussed progesterone effects following binding to the classical intracellular progesterone receptors A and B and several forms of membrane progesterone receptors, the modulation of intracellular signalling cascades and the interaction of progesterone reduced metabolites with neurotransmitter receptors. We next described our results involving animal models of human neuropathologies to elucidate the protective roles of progesterone.

Neuroprotection by steroids after neurotrauma in organotypic spinal cord cultures: a key role for progesterone receptors and steroidal modulators of GABA(A) receptors.

Progesterone is neuroprotective after spinal cord injury, however its mechanism of action remains unexplored. Here we used organotypic spinal cord slice cultures from 3 weeks-old mice to evaluate the mechanisms of neuroprotection by progesterone and its 5α-reduced metabolites. In vitro spinal cord injury, using a weight drop model, induced a decrease in the number of motoneurons.

Progesterone receptors: a key for neuroprotection in experimental stroke.

Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice.

Progesterone prevents nerve injury-induced allodynia and spinal NMDA receptor upregulation in rats.

Background: Peripheral nerve injury-evoked neuropathic pain still remains a therapeutic challenge. Recent studies support the notion that progesterone, a neuroactive steroid, may offer a promising perspective in pain modulation.

Objectives: Evaluate the effect of progesterone administration on the development of neuropathic pain-associated allodynia and on the spinal expression of N-Methyl-D-Aspartate Receptor subunit 1 (NR1), its phosphorylated form (pNR1), and the gamma isoform of protein kinase C (PKCγ), all key players in the process of central sensitization, in animals subjected to a sciatic nerve constriction.

Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury.

Reactive gliosis, demyelination and proliferation of NG2+ oligodendrocyte precursor cells (OPC) are common responses to spinal cord injury (SCI). We previously reported that short-term progesterone treatment stimulates OPC proliferation whereas chronic treatment enhances OPC differentiation after SCI. Presently, we further studied the proliferation/differentiation of glial cells involved in inflammation and remyelination in male rats with SCI subjected to acute (3 days) or chronic (21 days) progesterone administration.