Major depressive disorder is one of the most prevalent mental health disorders. Monoamine-based antidepressants were the first drugs developed to treat major depressive disorder. More recently, ketamine and other analogues were introduced as fast-acting antidepressants. Unfortunately, currently available therapeutics are inadequate; lack of efficacy, adverse effects, and risks leave patients with limited treatment options. Efforts are now focused on understanding the etiology of depression and identifying novel targets for pharmacological treatment. In this review, we discuss promising novel pharmacological targets for the treatment of major depressive disorder. Targeting receptors including N-methyl-D-aspartate receptors, peroxisome proliferator-activated receptors, G-protein-coupled receptor 39, metabotropic glutamate receptors, galanin and opioid receptors has potential antidepressant effects. Compounds targeting biological processes: inflammation, the hypothalamic-pituitary-adrenal axis, the cholesterol biosynthesis pathway, and gut microbiota have also shown therapeutic potential. Additionally, natural products including plants, herbs, and fatty acids improved depressive symptoms and behaviors. In this review, a brief history of clinically available antidepressants will be provided, with a primary focus on novel pharmaceutical approaches with promising antidepressant effects in preclinical and clinical studies.

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Novel Pharmacological Approaches to the Treatment of Depression

The proliferation, differentiation, and migration of neural precursor cells occur not only during embryonic development but also within distinct regions of the adult brain through the process of adult neurogenesis. As neurogenesis can potentially regulate brain cognition and neuronal plasticity, the factors that enhance neurogenesis can be attractive therapeutic targets for improving cognitive function and regulating neurodegenerative and neuropsychiatric disorders, including affective and mood disorders. Peroxisome proliferator-activated receptors (PPARs) are a class of ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARγ is a target for insulin sensitizers and plays an essential role in regulating various metabolic processes, including adipogenesis and glucose homeostasis. Interestingly, evidence demonstrates the role of PPARγ activation in regulating neurogenesis. The pharmacological activation of PPARγ using specific ligands increases the proliferation and differentiation of neural stem cells in specific brain regions, including the hippocampus, and prevents neurodegeneration and improves cognition and anxiety/depression-like behaviors in animal models. We summarize here recent reports on the role of PPARγ in adult neurogenesis, as well as the mechanisms involved, and suggest that PPARγ can serve as a potential therapeutic target for neurological and/or neurodegenerative diseases.

Peroxisome proliferator-activated receptor gamma: a novel therapeutic target for cognitive impairment and mood disorders that functions via the regulation of adult neurogenesis

Role of JAK-STAT and PPAR-Gamma Signalling Modulators in the Prevention of Autism and Neurological Dysfunctions

The β-adrenergic receptor blocker and anti-inflammatory drug propranolol mitigates brain cytokine expression in a long-term model of Gulf War Illness.

Background. Donor-derived cell-free DNA (dd-cfDNA) is a biomarker validated to detect rejection when measured to assess kidney allograft dysfunction. However, it remains unclear whether routine surveillance with dd-cfDNA provides additional information over standard monitoring of kidney allografts with creatinine and donor-specific antibodies (DSAs), particularly among those with little suspicion of rejection or injury. We investigated the value of measuring dd-cfDNA in patients with preserved allograft function and describe its association with future events. Methods. Three-hundred seventeen kidney transplant recipients with a creatinine ≤1.5 mg/dL, no current DSA, and no prior rejection were assessed with dd-cfDNA and categorized into low (dd-cfDNA <0.5%; n = 239), moderate (dd-cfDNA 0.5% to <1.0%; n = 43), and high (dd-cfDNA ≥1.0%; n = 35) groups. The occurrence of rejection, DSA, graft loss, and change in estimated glomerular filtration rate over time after dd-cfDNA assessment was compared. Results. Over follow-up, rejections were more commonly found among patients with high vs low dd-cfDNA (17% versus 5%; P = 0.01); a similar nonsignificant trend was observed among patients with moderate compared to low dd-cfDNA (12% versus 5%; P = 0.13). DSA development was uncommon and not different between groups (low: 4%; moderate: 3%; high: 0%; P = 0.52). There was only 1 graft loss in a patient with low dd-cfDNA, and dd-cfDNA was not associated with graft dysfunction over time. Conclusions. Most patients with elevated dd-cfDNA in conjunction with preserved allograft function remained stable over follow-up without deterioration in function or graft loss. Studies are needed to differentiate patients with elevated dd-cfDNA who will develop adverse outcomes from those who will remain clinically stable.

An Assessment of the Value of Donor-derived Cell-free DNA Surveillance in Patients With Preserved Kidney Allograft Function

Background Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI). Methods Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naive rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naive, GWE and GWE-ROSI. Results Compared to naive rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities. Conclusion This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.

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The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

Background Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for the early detection of organ transplant rejection and other causes of graft injury. For nonrejection renal injuries, there is little information about the performance characteristics of this biomarker. We highlight some of the possible causes of kidney injury that may arise in patients with normal dd-cfDNA levels. Methods We performed a retrospective analysis of solitary renal transplant cases between January 2017 and November 2019. Those who had an abnormal laboratory or pathological finding within 1 mo of a normal dd-cfDNA test were selected. Subgroups were stratified for those who had normal or abnormal/rising serum creatinine, and differences between the groups were analyzed. Results Of 414 individuals who received a kidney transplant, 24 (7.5%) had a total of 41 normal dd-cfDNA values and 51 abnormal laboratory tests or histologic findings. The most common graft-injuring event was BK virus viremia (24 of 51). Other abnormal findings included urinary traction infections (n = 4), CMV viremia (n = 4), and biopsies demonstrating antibody-mediated rejection (AMR) (n = 2), T cell-mediated rejection (n = 1), focal segmental glomerulosclerosis (n = 2), nondonor-specific antibody chronic AMR (n = 1), and interstitial fibrosis and tubular atrophy (n = 7). Subgroup analysis of those with normal dd-cfDNA and normal/stable versus abnormal/rising creatinine showed that BK virus viremia was the most common abnormal finding in both groups at 53% and 38% respectively. On biopsy, 1 case of acute T cell-mediated rejection (1B and 2B) was seen with normal/stable creatinine, whereas 1 of nonspecific C4d focally positive and 1 of nondonor-specific antibody AMR were seen with abnormal/rising creatinine. Conclusions Low levels of serum dd-cfDNA do not preclude detection of active graft-injuring events and that subclinical injuries may be developing. Context is important in the interpretation of dd-cfDNA, so renal biopsy remains a part of the diagnostic pathway for allograft dysfunction and maintenance of allograft health.

Causes of Renal Allograft Injury in Recipients With Normal Donor-derived Cell-free DNA.

BackgroundPercutaneous drainage as the initial procedure for severe pancreatitis (SP) may not always be optimal. Our aim was to identify the characteristics of patients who failed percutaneous drai...

Kevin Kim

Papers

The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.

Causes of Renal Allograft Injury in Recipients With Normal Donor-derived Cell-free DNA.

Characteristics and Outcomes of Drainage Versus Surgery First in Severe Pancreatitis.