Anavex Life Sciences Corp (AVXL)

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Anavex 2-73 and/or Anavex 3-71 could be a safe and effective treatment for PTSD

Activation of Sigma-1 receptor ameliorates anxiety-like behavior and cognitive impairments in a rat model of post-traumatic stress disorder.
Ji LL1, Peng JB1, Fu CH1, Cao D1, Li D1, Tong L2, Wang ZY3.
Author information
1
Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, People's Republic of China.
2
Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, People's Republic of China. Electronic address: [e-mail].
3
Department of Anatomy, College of Basic Medical Sciences, China Medical University, Shenyang, People's Republic of China. Electronic address: [e-mail].
Abstract
Among learning and memory processes, fear memories are crucial in some psychiatric disorders like post-traumatic stress disorder (PTSD). Accumulating evidence shows that the sigma-1 receptor (Sig-1R) has comprehensive involvement in cognitive impairment and neuroprotective effects. It has also been reported that BDNF appears to enhance extinction of fear in anxiety disorders via the MAPK signaling cascade. However, it remains unclear whether BDNF-TrkB-MAPK pathway may be mechanistically involved in the therapeutic effect of sigma-1 receptor in the development of PTSD. To address this question, rats were subjected to a classical single-prolonged stress procedure (SPS) and kept undisturbed for 7 days. After that, rats were re-stressed by re-exposure to the forced swim component of SPS (RSPS). Behavior tests were subsequently performed to assess anxiety and cognitive impairments. Furthermore, we analyzed the expression of BDNF and the phosphorylation of TrkB and three MAPK pathways, namely, the ERK, JNK and p38. We found that the levels of BDNF and p-TrkB were increased following the RSPS procedure, which were reversed by the administration of PRE-084. Meanwhile, among the three MAPK signaling pathways, only the p-ERK expression was increased following the RSPS procedure. Collectively, our results indicate that BDNF-TrkB-ERK signaling pathway may be involved in the activation of sigma-1 receptor to yield therapeutic benefits for PTSD.

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Hippocampal Endoplasmic Reticulum Stress: Novel Target in PTSD Pharmacotherapy?
Agung Nova Mahendra1 and I. Nyoman Adi Jaya Putra2

1Department of Pharmacology and Therapy, and Division of Drug Development and Laboratory Animal, Integrated Biomedical Laboratory Unit, Faculty of Medicine, Udayana University.

2Lecturer of Psycholinguistics, English Language Education, Faculty of Language and Arts, Ganesha University of Education.

Corresponding Author E-mail: [e-mail]

DOI : http://dx.doi.org/10.13005/bpj/1488

Abstract:

Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurred in individual who had experienced severe traumatic stresses. This disorder is accompanied by functional impairments in daily activities, comorbidities (such as depression) and increased risk of suicide. Some studies also demonstrate that PTSD is linked to structural and functional impairment of hippocampus. Hippocampal defect has been found in PTSD model, especially in single-prolonged stress (SPS)-induced animal model, with excessive or prolonged endoplasmic reticulum (ER) stress-induced neuronal apoptosis as a proposed mechanism. Unfortunately, this cellular event has not been studied and validated in humans suffering from PTSD. Two chaperones known as glucose-regulated protein 78 (GRP78) and sigma-1 receptor (Sig1R) have been demonstrated to exhibit central roles in mitigating the effects of severe ER stress on cell survival. Several selective serotonin-reuptake inhibitors (SSRIs), such as fluvoxamine and sertraline, are also found to be an agonist and antagonist of sigma-1 receptor (Sig1R) in animal brain cells, respectively. There is also link between antidepressant use and risk of suicidal ideation. Therefore, the authors propose that hippocampal ER stress may be involved in PTSD pathobiology. Pharmacodynamics of currently available therapeutic agents for PTSD and its comorbidities on hippocampal ER stress should be clearly elucidated to promote therapy optimization and drug development.

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Donepezil Helps Alleviate Nightmares Associated With Posttraumatic Stress Disorder and Other Psychiatric Conditions: A Report of 4 Cases
Mohammad Farooque, MD, PhDcorresponding author
Author information Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
To the Editor: Many patients with the diagnosis of posttraumatic stress disorder (PTSD) or a history of emotional trauma report recurrent nightmares. Though there is a widespread prevalence of nightmares in patients with various psychiatric conditions, there are few treatments available to treat or manage this symptom.1,2 Prazosin has been shown in some studies to help with nightmares related to PTSD.1–7 Donepezil is approved by the US Food and Drug Administration for mild-to-severe Alzheimer’s dementia.8,9 Donepezil is a reversible inhibitor of the acetylcholinesterase enzyme. The enzyme acetylcholinesterase breaks down the neurotransmitter acetylcholine. In this way, donepezil may allow a greater concentration of acetylcholine in the brain, thereby improving cholinergic function.10 The following is a series of cases in which nightmares in patients with various diagnoses responded well to 10 mg of donepezil at bedtime.

Case 1. Mr A, a 63-year-old white retired captain of the US Army, had participated in the Vietnam War and Operation Desert Storm. He has a history of PTSD (DSM-IV criteria) and opioid abuse, which started after he was put on treatment with opioids due to war injuries. He had participated in combat several times during his active duty service. Mr A had a history of recurrent nightmares. Most of his nightmares were related to wartime situations and almost always included a situation in which he was not able to escape, could not move during the dream, and felt awake during the dream. At his 1-month outpatient follow-up after he was started on donepezil 10 mg/d, his nightmares were very few, and in fact he reported some pleasant dreams after being placed on donepezil treatment.

Case 2. Ms B, a 64-year-old divorced white woman diagnosed with hepatitis C, was admitted as an inpatient for major depressive disorder, recurrent, severe without psychotic features (DSM-IV criteria), and an overdose. She stated she had been depressed for years and had inability to sleep because of recurrent nightmares that she was dying, which woke her up. She was also having nightmares about something terrible happening to her. The day after donepezil 10 mg daily at bedtime was started, she reported that she was having pleasant dreams, including one in which she was walking her dog in her neighborhood.

Case 3. Mr C, a 41-year-old Iraqi immigrant, was tortured during Saddam Hussein’s regime and had a diagnosis of PTSD (DSM-IV criteria). He reported waking up screaming and having horrible nightmares. At his 1-month outpatient follow-up after he was started on donepezil 10 mg/d, he reported that his nightmares significantly subsided and his sleep improved.

Case 4. Ms D, a 56-year-old white woman, had a history of bipolar I disorder (DSM-IV criteria). She reported repeated nightmares. At her 1-month outpatient follow-up after she was started on donepezil 10 mg/d, she reported significant improvement in her nightmares.

Acetylcholine plays an important role in the sleep-wake cycle. Cholinergic projections from the forebrain act as a relay center for the brainstem-cortical arousal system and modulate cortical activity and thus promote wakefulness or rapid eye movement (REM) sleep.11–13 We do not know the exact mechanism of action of donepezil and the improvement in the nightmares. However, considering that most of the nightmares are associated with REM sleep, there could be an intimate association of level of acetylcholine available and nightmares. On the basis of successful management of nightmares in these few cases with donepezil, we hypothesize that the low levels of acetylcholine could lead to sleep disturbance and nightmares. These results are only preliminary, and more controlled studies are needed to validate or reject this hypothesis and address the problem of nightmares in the population of psychiatric patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505136/

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