Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series.

PURPOSE: The aim of the study was to assess the effectiveness, tolerability, and safety of oral ketamine as an antidepressant treatment in adults with treatment-resistant depression. METHODS: We reviewed retrospective data on 22 patients with treatment-resistant depression, who failed at least 3 adequate antidepressant treatment trials and 1 adequate trial of repetitive transcranial magnetic stimulation; subsequently, they received open-label treatment with oral ketamine, commenced at a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to response and tolerability. The primary outcome measure was the Beck Depression Inventory II, which was used to rate subjective mood improvement at baseline and then at each follow-up visit. Data about adverse effects related to ketamine and a self-harm risk assessment were also obtained. FINDINGS: Over the course of treatment, 18% of the patients showed greater than 50% reduction in the Beck Depression Inventory II scores, 14% reported partial improvement in mood symptoms, while 45% had no response to ketamine and 23% showed a mild worsening in their depressive symptoms. The most frequent adverse effects were acute dissociation, dizziness, blurred vision, numbness and sedation. Neither serious adverse effects, nor any cases of abuse or dependence were observed. CONCLUSIONS: Although this case series found oral ketamine to be safe and well tolerated, the findings also showed rather modest effectiveness of oral ketamine in treatment-resistant depression, with only approximately 30% reporting some benefit and approximately 70% reporting no change or worsening of mood. However, bearing in mind the limitations of this small, open-label case series, further exploration of the effectiveness of oral ketamine is warranted.

PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria.

Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved in CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to have immunomodulatory effects in a variety of disease models. Here we report that adjunctive therapy with PPARγ agonists improved survival and long-term neurocognitive outcomes in the Plasmodium berghei ANKA experimental model of CM. Compared to anti-malarial therapy alone, PPARγ adjunctive therapy administered to mice at the onset of CM signs, was associated with reduced endothelial activation, and enhanced expression of the anti-oxidant enzymes SOD-1 and catalase and the neurotrophic factors brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brains of infected mice. Two months following infection, mice that were treated with anti-malarials alone demonstrated cognitive dysfunction, while mice that received PPARγ adjunctive therapy were completely protected from neurocognitive impairment and from PbA-infection induced brain atrophy. In humans with P. falciparum malaria, PPARγ therapy was associated with reduced endothelial activation and with induction of neuroprotective pathways, such as BDNF. These findings provide insight into mechanisms conferring improved survival and preventing neurocognitive injury in CM, and support the evaluation of PPARγ agonists in human CM.