Neutrophil-to-lymphocyte ratio as a predictive biomarker for early diagnosis of depression: A narrative review.

Depression is a mood disorder that causes persistent feelings of sadness, hopelessness, loss of interest, and decreased energy. Early diagnosis of depression can improve its negative impacts and be effective in its treatment. Previous studies have indicated that inflammation plays an important role in the initiation and development of depression, hence, various inflammatory biomarkers have been investigated for early diagnosis of depression, the most popular of which are blood biomarkers. The Neutrophil to lymphocyte ratio (NLR) may be more informative in the early diagnosis of depression than other widely used markers, such as other leukocyte characteristics or interleukins. Considering the importance of early diagnosis of depression and the role of NLR in early diagnosis of depression, our paper reviews the literature on NLR as a diagnostic biomarker of depression, which may be effective in its treatment. Various studies have shown that elevated NLR is associated with depression, suggesting that NLR may be a valuable, reproducible, easily accessible, and cost-effective method for the evaluation of depression and it may be used in outpatient clinic settings. Closer follow-up can be performed for these patients who have higher NLR levels. However, it seems that further studies on larger samples, taking into account important confounding factors, and assessing them together with other inflammatory markers are necessary to draw some conclusive statements.

Isobolographic analysis of the antidepressant interaction in two-drug combinations of citalopram, bupropion, and scopolamine in mice.

Depression and anxiety are psychiatric diseases that commonly occur together, and the patient burden and complexity increase when both are present. Comorbid anxiety and depression are often more resistant to common drug treatments such as antidepressants. Combination therapy is a suggested approach in treating these patients, where a decline of doses could reduce undesirable outcomes and still achieve optimal effects. We, therefore, conducted a preclinical study to assess the effect of two-drug combinations of citalopram, bupropion, and scopolamine on anxiety- and antidepressive-like behaviors in male NMRI mice and aimed to determine the nature of the interaction between components. Anxiety- or antidepressive-like activity of mice was assessed by the hole-board or forced swim test (FST), respectively. Our results revealed that citalopram (0.01-0.25 mg/kg; i.p.), bupropion (1-9 mg/kg; i.p.), or scopolamine (0.01-0.1 mg/kg; i.p.) diminished immobility time in the FST, suggesting an antidepressive-like effect. Citalopram decreased dead-dip counts in the hole-board, indicating an anxiogenic-like activity. All two-drug combinations, at inactive doses, exerted an antidepressive-like behavior. Only bupropion/scopolamine combination increased head-dip counts compared to the bupropion/saline group. Isobolographic analysis revealed an antidepressive synergy effect between citalopram plus bupropion, and an antidepressive additive impact between scopolamine plus citalopram or bupropion. It should be noted that the higher dose of each drug alone declined locomotor activity, while two-drug combinations did not affect this parameter. These results suggest a stronger antidepressive effect for citalopram/bupropion combination than other two-drug combinations.

The effect of GABA-B receptors in the basolateral amygdala on passive avoidance memory impairment induced by MK-801 in rats.

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 µg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 µg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 µg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 µg/rat, baclofen at the doses of 0.001 and 0.01 µg/rat, and phaclofen at the doses of 0.001 and 0.01 µg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 µg/rat) and phaclofen (0.0001 µg/rat) restored the impairment effect of MK-801 (0.5 µg/rat) on memory. Also, both baclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 µg/rat) and phaclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 µg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.

Punicalagin effect on total sleep deprivation memory deficit in male Wistar rats.

Sleep deprivation has deteriorating effects on cognitive functions and activation of brain inflammation mechanisms has been reported by some studies following total sleep deprivation. Some studies have reported the health benefits of punicalagin, a main abstract from Punica granatum L., including those for the treatment of Alzheimer's disease. The antioxidant characteristic of punicalagin and the fact that sleep deprivation accelerates mediators of inflammation led us to further explore the possible neuroprotective role of punicalagin in total sleep deprivation memory impairment in a rat model. In this study, male Wistar rats were implanted with a canula in the lateral ventricle to receive intracerebroventricular injections (drug or vehicle). The animals were trained for the passive avoidance test and then received intracerebroventricular injections of different doses of punicalagin (0.001, 0.01, or 0.1 µg/rat). Then, they were placed in the sleep deprivation apparatus for 24 hours and tested afterwards for memory retrieval and locomotion. Our results indicated that 24 hours of total sleep deprivation impaired memory processes. PG microinjection before TSD did not prevent the deteriorating effect of total sleep deprivation on memory, and only showed a tendency of restoring the memory impairment. Comparison of the locomotor activity between the animals in different groups showed a significant increase in the total sleep deprivation sham groups that received two of the highest doses of punicalagin. Considering the reported beneficial actions of PG by other studies, further investigation is needed into the possible effects of PG in memory alterations.

The interaction effect of sleep deprivation and cannabinoid type 1 receptor in the CA1 hippocampal region on passive avoidance memory, depressive-like behavior and locomotor activity in rats.

Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 µg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 µg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 µg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.

The protective effect of alpha lipoic acid (ALA) on social interaction memory, but not passive avoidance in sleep-deprived rats.

Sleep is involved in maintaining energy, regulating heat, and recovering tissues. Furthermore, proper cognitive functions need sufficient sleep. Many studies have revealed the impairment effect of sleep deprivation (SD) on cognitive functions including learning and memory. Alpha lipoic acid (ALA) is a potent free radical scavenger, biological antioxidant, and neuroprotective agent. Furthermore, ALA improves learning and memory performance, decreases oxidative stress, and enhances antioxidant biomarkers. In this study, we aimed to investigate the effect of ALA on social interaction and passive avoidance memories in sleep-deprived rats. Total sleep deprivation (TSD) apparatus was used to induce SD (for 24 h). Three-chamber paradigm test and shuttle box apparatus were used to evaluate social interaction and passive avoidance memory, respectively. Rats' locomotor apparatus was used to assess locomotion. ALA was administered intraperitoneally at doses of 17 and 35 mg/kg for 3 consecutive days. The results showed SD impaired both types of memories. ALA at the dose of 35 mg/kg restored social interaction memory in sleep-deprived rats; while, at the dose of 17 mg/kg attenuated impairment effect of SD. Moreover, ALA at the dose of 35 mg/kg impaired passive avoidance memory in sham-SD rats and at both doses did not rescue passive avoidance memory in sleep-deprived rats. In conclusion, ALA showed impairment effect on passive avoidance memory, while improved social interaction memory in sleep-deprived rats.

Better antidepressant efficacy of mecamylamine in combination with L-NAME than with L-arginine.

Aff ;ective disorders, including anxiety and mood disorders, are a constellation of psychiatric diseases that aff ;ect over 10 % of the world's population. It has been proposed that drugs that change nicotinic acetylcholine receptor (nAChR) activity can affect mood- and anxiety-related behaviors. Also, neuronal nitric oxide synthase (nNOS) is closely associated with the pathophysiology of these disorders. To limit the potential adverse effects of alteration in cholinergic and nitric oxide (NO) systems, we investigated the combined efficacy of subthreshold doses of nAChR antagonist mecamylamine and NO ligands (L-arginine as agonist and l-NAME as an antagonist) on depression- and anxiety-related behaviors in male NMRI mice. Depression-related behaviors using the forced swim test (FST) and anxiety-like activity using the hole-board test were assessed. In our results, mecamylamine (3 mg/kg) showed antidepressant-like properties, and it also tended to have anxiolytic-like effects, though not significant. Concomitant treatment of subthreshold doses of mecamylamine (1 mg/kg) and l-arginine (25 mg/kg), l-NAME (1 mg/kg), or l-arginine/L-NAME were antidepressive. In contrast, l-arginine/L-NAME alone or in associated with mecamylamine showed anxiogenic-like efficacy. Isobolographic analysis exhibited an additive antidepressant effect of the combined subthreshold doses of mecamylamine and l-arginine, and a synergistic antidepressant effect of the combined subthreshold doses of mecamylamine and l-NAME. It should be noted that mecamylamine (3 mg/kg) elicited hypolocomotion. Our results suggest that mecamylamine produces a better antidepressant efficacy in combination with l-NAME than with l-arginine.

The Effects of Embryonic Cerebrospinal Fluid on The Viability and Neuronal Differentiation of Adipose Tissue-Derived Stem Cells in Wistar Rats.

OBJECTIVE: The embryonic cerebrospinal fluid (e-CSF) contains various growth factors and morphogens. Recent studies showed that e-CSF plays significant roles in embryonic brain development. Adipose tissue-derived stem cells (ADSCs) have a mesodermal origin that can be differentiated into mesodermal and ectodermal lineages. This study aimed to evaluate the effects of e-CSF on the proliferation, viability, and neural differentiation of ADSCs in rats. MATERIALS AND METHODS: In this experimental study, adipose tissue was dissected out from the inguinal region of adult male rats. Then, ADSCs were isolated by enzymatic digestion from adipose tissues and mesenchymal cells were confirmed using the flow cytometry analysis that measured the cell surface markers including CD90, CD44, CD73, CD105, CD34, CD45, and CD11b. The multi-potential characteristics of ADSCs were assessed by osteogenic and adipogenic potentials of these cells. Under suitable in vitro conditions, ADSCs were cultured in DMEM supplemented with and without additional 10% e-CSF. These fluids were collected from Wistar rats at the E17, E18, and E19 gestational ages. Cellular proliferation and viability were determined using the MTT assay. Immunocytochemistry was used to study the expression of ß-III tubulin in ADSCs. The neurite outgrowth of cultured cells was assessed using the ImageJ software. RESULT: The results of the present study demonstrated that the viability of ADSCs in cell culture conditioned with E17 and E18 e-CSF were significantly increased in comparison with controls. Cultured cells treated with e-CSF from E18 and E19 established neuronal-like cells bearing long process, whereas no process was observed in the control groups or cultured cells treated with E17 e-CSF. CONCLUSION: This study showed that e-CSF has the ability to induce neuronal differentiation and viability in ADSCs. Our data support a significant role of e-CSF as a therapeutic strategy for the treatment of neurodegenerative diseases.

Additive interaction between scopolamine and nitric oxide agents on immobility in the forced swim test but not exploratory activity in the hole-board.

RATIONALE: The muscarinic cholinergic antagonist scopolamine has received an attention due to its unique antidepressant effects. However, the considerable adverse effects on nervous system limit the use of scopolamine as a psychiatric drug. OBJECTIVE: In order to overcome the limitations and increase the therapeutic effects of scopolamine, we decided to examine the effects of joint administration of sub-effective dose of scopolamine and the sub-effective dose of a nitric oxide (NO) precursor L-Arginine or a non-selective nitric oxide synthase (NOS) inhibitor L-NAME on depression- and anxiety-related behaviors in male NMRI mice. METHODS: To this aim, animal behavior was assessed in the forced swim test (FST) and hole-board apparatus. RESULTS: Scopolamine (0.05 mg/kg) significantly decreased immobility time in the FST, suggesting an antidepressant-like effect. Moreover, L-Arginine (50 mg/kg) produced an antidepressant-like response in the FST and decreased head-dip counts in the hole-board apparatus, indicating an anxiety-like effect. The same doses of scopolamine and L-Arginine decreased the locomotor activity in mice. Joint administration of sub-effective dose of scopolamine (0.01 mg/kg) with a low dose of L-Arginine (25 mg/kg) or L-NAME (1 mg/kg) induced a profound antidepressant-like effect in the FST. These drug combinations did not influence on anxiety-related behaviors. Meanwhile, L-NAME alone did not alter the performance of mice in the FST and hole-board. Isobolographic analysis revealed an additive effect for scopolamine and L-Arginine or L-NAME. CONCLUSION: Data suggests that NO agents could positively impact the therapeutic profile of scopolamine, because they might be useful for inducing antidepressant-like effect associated to scopolamine.