Protective effects of the neurosteroid allopregnanolone in a mouse model of spontaneous motoneuron degeneration

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by progressive death of motoneurons. The Wobbler (WR) mouse is a preclinical model sharing neuropathological similarities with human ALS. We have shown that progesterone (PROG) prevents the progression of motoneuron degeneration. We now studied if allopregnanolone (ALLO), a reduced metabolite of PROG endowed with gabaergic activity, also prevents WR neuropathology. Sixty-day old WRs remained untreated or received two steroid treatment regimens in order to evaluate the response of several parameters during early or prolonged steroid administration. ALLO was administered s.c. daily for 5days (4mg/kg) or every other day for 32days (3, 3mg/kg), while another group of WRs received a 20mg PROG pellet s.c. for 18 or 60days. ALLO administration to WRs increased ALLO serum levels without changing PROG and 5 alpha dihydroprogesterone (5α-DHP), whereas PROG treatment increased PROG, 5α-DHP and ALLO. Untreated WRs showed higher basal levels of serum 5α-DHP than controls. In the cervical spinal cord we studied markers of oxidative stress or associated to trophic responses. These included nitric oxide synthase (NOS) activity, motoneuron vacuolation, MnSOD immunoreactivity (IR), brain derived neurotrophic factor (BDNF) and TrkB mRNAs, p75 neurotrophin receptor (p75NTR) and, cell survival or death signals such as pAKT and the stress activated kinase JNK. Untreated WRs showed a reduction of MnSOD-IR and BDNF/TrkB mRNAs, associated to high p75NTR in motoneurons, neuronal and glial NOS hyperactivity and neuronal vacuolation. Also, low pAKT, mainly in young WRs, and a high pJNK in the old stage characterized WŔs spinal cord. Except for MnSOD and BDNF, these alterations were prevented by an acute ALLO treatment, while short-term PROG elevated MnSOD. Moreover, after chronic administration both steroids enhanced MnSOD-IR and BDNF mRNA, while attenuated pJNK and NOS in glial cells. Long-term PROG also increased pAKT and reduced neuronal NOS, parameters not modulated by chronic ALLO. Clinically, both steroids improved muscle performance. Thus, ALLO was able to reduce neuropathology in this model. Since high oxidative stress activates p75NTR and pJNK in neurodegeneration, steroid reduction of these molecules may provide adequate neuroprotection. These data yield the first evidence that ALLO, a gabaergic neuroactive steroid, brings neuroprotection in a model of motoneuron degeneration.

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD?

“…In female rats, knocking out the pregnane xenobiotic receptor (important for steroidogenesis) reduced hippocampal allopregnanolone concomitantly with a decrease in BDNF expression in the same brain area examined [66]. Chronic treatment with allopregnanolone restored impaired BDNF levels found in the spinal cord of a mouse model of motoneuron degeneration [67]. Low to moderate concentrations of allopregnanolone increased BDNF expression in vitro in response to neuronal damage induced by 6-hydroxydopamine (6-OHDA) administration [68].…”

Allopregnanolone: An overview on its synthesis and effects

“…242 Indeed, alteration of ALLO synthesis modulate status epilepticus dynamics. 243,244 In addition, protective effects have been reported in an experimental model of amyotrophic lateral sclerosis (ie, Wobbler mouse), 245 in PD experimental models, 246,247 as well as in a pilot clinical study performed in patients affected by fragile X-associated tremor/ataxia syndrome, where the ALLO treatment was reported to improve cognitive function and neurodegeneration. 248,249 In an animal model of Niemann-Pick type C disease, this neuroactive steroid has been demonstrated to delay the onset of neurological symptoms, increasing Purkinje and granule cell survival in the cerebellum, reducing cortical ganglioside accumulation, cholesterol accumulation and inflammation, and enhancing myelination.…”

The Role of Allopregnanolone Levels in Traumatic Brain Injury in Children and Adults and the Correlation of Its Levels with Computerized Tomography Images of the Brain

“…15 A study on Alzheimer patients reported that AP is the main element in neurogenic and regenerative therapies because it readily crosses the blood-brain barrier. 16 Reddy et al conducted a study on treatment-resistant epilepsy patients and observed that progesterone given to the patients in the second half of the menstrual cycle increased the AP levels, providing therapeutic benefits. 17 Similarly, there are studies demonstrating the relationship of AP with several diseases Abbreviations: AP, allopregnanolone; GCS, Glasgow coma score; TBI, traumatic brain injury.…”