Early regeneration of axons following peripheral nerve injury is enhanced if p75NTR is eliminated from the surrounding pathway.

The common neurotrophin receptor, p75NTR , has been proposed to be an inhibitor of axon regeneration after peripheral nerve injury, but whether this effect is on the regenerating axons, immune cells migrating into the injury site, or cells in the pathway surrounding the axons is not clear. Cut nerves in mice expressing fluorescent proteins in axons were repaired with grafts from non-fluorescent hosts to study axon elongation when p75NTR was eliminated separately from axons and immune cells in the proximal stump of cut nerves, from cells in the regeneration pathway, or both. Two weeks later, axons from wild type mice regenerating into grafts devoid of p75NTR had elongated more than twice as far as axons in grafts from wild type mice. No enhancement of regeneration of axons in p75NTR knockout mice was observed, whether nerves were repaired with grafts from wild type mice or from p75NTR knockout mice. To evaluate whether inhibition of p75NTR could be used to improve regeneration, nerves in wild type mice repaired without grafts were exposed to a specific inhibitor of the p75NTR receptor, LM11A-31, at the time of nerve repair. This local blockade of p75NTR resulted in successful regeneration of axons of nearly three times as many motoneurons and reinnervation of twice as many muscle fibers by regenerating motor axons as untreated controls. Expression of p75NTR surrounding regenerating axons contributes to poor regeneration during the first 2 weeks after peripheral nerve injury. Inhibition of p75NTR might be a therapeutic target for treatments of peripheral nerve injuries.

Spontaneous Bacteroides fragilis spondylodiscitis in an elderly lady.

A 76-year-old woman presented following two episodes of unexplained falls at home. Blood cultures were positive for Bacteroides fragilis and following investigations she was diagnosed with L4/L5 spondylodiscitis confirmed on spine MRI. She was initially treated with intravenous metronidazole and flucloxacillin prior to switching to ceftriaxone with good results. No primary cause of B. fragilis bacteraemia was found in this case. B. fragilis is a rare cause of spondylodiscitis.

The Val66Met BDNF Polymorphism and Peripheral Nerve Injury: Enhanced Regeneration in Mouse Met-Carriers Is Not Further Improved With Activity-Dependent Treatment.

Activity-dependent treatments to enhance peripheral nerve regeneration after injury have shown great promise, and clinical trials implementing them have begun. Success of these treatments requires activity-dependent release of brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP) in the bdnf gene known as Val66Met, which is found in nearly one third of the human population, results in defective activity-dependent BDNF secretion and could impact the effectiveness of these therapies. Here, we used a mouse model of this SNP to test the efficacy of treadmill exercise in enhancing axon regeneration in animals both heterozygous (V/M) and homozygous (M/M) for the SNP. Axon regeneration was studied 4 weeks after complete transection and repair of the sciatic nerve in both male and female animals, using both electrophysiological and histological outcome measures. Regeneration was enhanced significantly without treatment in V/M mice, compared with wild type (V/V) controls. Unlike V/V mice, treatment of both V/M and M/M mice with treadmill exercise did not result in enhanced regeneration. These results were recapitulated in vitro using dissociated neurons containing the light-sensitive cation channel, channelrhodopsin. Three days after plating, neurites of neurons from V/M and M/M mice were longer than those of V/V neurons. In neurons from V/V mice, but not those from V/M or M/M animals, longer neurites were found after optogenetic stimulation. Taken together, Met-carriers possess an intrinsically greater capacity to regenerate axons in peripheral nerves, but this cannot be enhanced further by activity-dependent treatments.

The Role of BDNF in Peripheral Nerve Regeneration: Activity-Dependent Treatments and Val66Met.

Despite the ability of peripheral nerves to spontaneously regenerate after injury, recovery is generally very poor. The neurotrophins have emerged as an important modulator of axon regeneration, particularly brain derived neurotrophic factor (BDNF). BDNF regulation and signaling, as well as its role in activity-dependent treatments including electrical stimulation, exercise, and optogenetic stimulation are discussed here. The importance of a single nucleotide polymorphism in the BDNF gene, Val66Met, which is present in 30% of the human population and may hinder the efficacy of these treatments in enhancing regeneration after injury is considered. Preliminary data are presented on the effectiveness of one such activity-dependent treatment, electrical stimulation, in enhancing axon regeneration in mice expressing the met allele of the Val66Met polymorphism.

Estrogens and the cognitive symptoms of schizophrenia: Possible neuroprotective mechanisms.

Schizophrenia is a complex neuropsychiatric illness with marked sex differences. Women have later onset and lesser symptoms, which has led to the hypothesis that estrogens are protective in schizophrenia. Cognitive dysfunction is a hallmark of the disease and the symptom most correlated with functional outcome. Here we describe a number of mechanisms by which estrogens may be therapeutic in schizophrenia, with a focus on cognitive symptoms. We review the relationship between estrogens and brain derived neurotrophic factor, neuroinflammation, NMDA receptors, GABA receptors, and luteinizing hormone. Exploring these pathways may enable novel treatments for schizophrenia and a greater understanding of this devastating disease.

Estradiol attenuates the cognitive deficits in the novel object recognition task induced by sub-chronic phencyclidine in ovariectomized rats.

Clinical studies have suggested that estrogens may affect the symptoms of schizophrenia. The novel object recognition task (NORT) in female rats treated with sub-chronic phencyclidine (PCP) was used as an animal model of the cognitive deficits in schizophrenia. The current studies investigated whether chronic estradiol (E) could alleviate sub-chronic PCP-induced cognitive deficits in the NORT. Adult Sprague-Dawley rats were ovariectomized (ovx) and treated with either sub-chronic PCP (2 mg/kg bidaily i.p. for seven days), or with 0.9% saline and their object recognition memory was tested with the NORT using an acquisition trial, 1 min inter-trial interval, and retention trial. Sub-chronic PCP administration did not reliably affect behavior in the acquisition trial but significantly impaired object recognition in the retention trial for 1-2 and 27-29 weeks. Ovx females spent significantly (p<0.05) more time exploring the novel compared to the familiar object, whereas PCP-treated ovx females did not. This effect of PCP was attenuated by long-lasting E capsules implanted prior to PCP treatment. PCP-treated females implanted with E again spent significantly more time exploring the novel compared to the familiar object (p<0.01). When ovx rats were treated with sub-chronic PCP and a long-lasting E capsule was implanted either before or after PCP treatment, estradiol alleviated the PCP-induced deficits when administered in either regimen (p=0.01 and p=0.047 respectively). These data suggest that further exploration of estradiol as a possible therapeutic compound to treat the cognitive deficits of schizophrenia is warranted.