Neuroprotective Effects of Testosterone in Male Wobbler Mouse, a Model of Amyotrophic Lateral Sclerosis.

Patients suffering of amyotrophic lateral sclerosis (ALS) present motoneuron degeneration leading to muscle atrophy, dysphagia, and dysarthria. The Wobbler mouse, an animal model of ALS, shows a selective loss of motoneurons, astrocytosis, and microgliosis in the spinal cord. The incidence of ALS is greater in men; however, it increases in women after menopause, suggesting a role of sex steroids in ALS. Testosterone is a complex steroid that exerts its effects directly via androgen (AR) or Sigma-1 receptors and indirectly via estrogen receptors (ER) after aromatization into estradiol. Its reduced-metabolite 5α-dihydrotestosterone acts via AR. This study analyzed the effects of testosterone in male symptomatic Wobblers. Controls or Wobblers received empty or testosterone-filled silastic tubes for 2 months. The cervical spinal cord from testosterone-treated Wobblers showed (1) similar androgen levels to untreated control and (2) increased levels of testosterone, and its 5α-reduced metabolites, 5α- dihydrotestosterone, and 3ß-androstanediol, but (3) undetectable levels of estradiol compared to untreated Wobblers. Testosterone-treated controls showed comparable steroid concentrations to its untreated counterpart. In testosterone- treated Wobblers a reduction of AR, ERα, and aromatase and high levels of Sigma-1 receptor mRNAs was demonstrated. Testosterone treatment increased ChAT immunoreactivity and the antiinflammatory mediator TGFß, while it lessened vacuolated motoneurons, GFAP+ astrogliosis, the density of IBA1+ microgliosis, proinflammatory mediators, and oxidative/nitrosative stress. Clinically, testosterone treatment in Wobblers slowed the progression of paw atrophy and improved rotarod performance. Collectively, our findings indicate an antiinflammatory and protective effect of testosterone in the degenerating spinal cord. These results coincided with a high concentration of androgen-reduced derivatives after testosterone treatment suggesting that the steroid profile may have a beneficial role on disease progression.

Mineralocorticoid Receptors, Neuroinflammation and Hypertensive Encephalopathy.

Worldwide, raised blood pressure is estimated to affect 35-40% of the adult population and is a main conditioning factor for cardiovascular diseases and stroke. Animal models of hypertension have provided great advances concerning the pathophysiology of human hypertension, as already shown for the deoxycorticosterone-salt treated rat, the Dahl-salt sensitive rat, the Zucker obese rat and the spontaneously hypertensive rat (SHR). SHR has been widely used to study abnormalities of the brain in chronic hypertension. This review summarises present and past evidence that in the SHR, hypertension causes hippocampal tissue damage which triggers a pro-inflammatory feedforward cascade affecting this vulnerable brain region. The cascade is driven by mineralocorticoid receptor (MR) activation responding to endogenous corticosterone rather than aldosterone. Increased MR expression is a generalised feature of the SHR which seems to support first the rise in blood pressure. Then oxidative stress caused by vasculopathy and hypoxia further increases MR activation in hippocampal neurons and glia cells, activates microglia activation and pro-inflammatory mediators, and down-regulates anti-inflammatory factors. In contrast to MR, involvement of the glucocorticoid receptor (GR) in SHR is less certain. GR showed normal expression levels and blockage with an antagonist failed to reduce blood pressure of SHR. The findings support the concept that MR:GR imbalance caused by vasculopathy causes a switch in MR function towards a proverbial "death" receptor.

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. METHODS: Male Sprague-Dawley rats were subjected to a sciatic nerve single ligature constriction and treated with daily subcutaneous injections of progesterone (16 mg/kg) or vehicle. The development of hindpaw mechanical and thermal allodynia was assessed using the von Frey and Choi tests, respectively. Twenty two days after injury, the number of neuronal profiles exhibiting NR1, pNR1, or PKCγ immunoreactivity was determined in the dorsal horn of the lumbar spinal cord. RESULTS: Injured animals receiving progesterone did not develop mechanical allodynia and showed a significantly lower number of painful responses to cold stimulation. In correlation with the observed attenuation of pain behaviors, progesterone administration significantly reduced the number of NR1, pNR1, and PKCγ immunoreactive neuronal profiles. CONCLUSIONS: Our results show that progesterone prevents allodynia in a rat model of sciatic nerve constriction and reinforce its role as a potential treatment for neuropathic pain.

Progesterone and the spinal cord: good friends in bad times.

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.