Edith Araceli Cabrera-Muñoz

In amnestic mild cognitive impairment (aMCI), neuroinflammation evolves during disease progression, affecting microglial function and potentially accelerating the pathological process. Currently, no effective treatment exists, leading to explorations of various symptomatic approaches, though few target the underlying physiological mechanisms. Modulating inflammatory processes may be critical in slowing disease progression. Cognitive stimulation (CS) and transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (l-DLPFC) show promise, but the results are heterogeneous. Thus, a randomized, double-blind, placebo-controlled clinical trial is currently underway. The first-stage results were examined after three weeks of intervention in two groups: active tDCS combined with CS and sham tDCS combined with CS. Twenty-two participants underwent two assessments: T0 (baseline) and T1 (after 15 sessions of tDCS, active or sham, and 9 sessions of CS). The results demonstrated that CS improved cognition, increased brain-derived neurotrophic factor (BDNF) levels, and reduced peripheral proinflammatory cytokine levels (interleukin IL-6 and chemokine CX3CL1) in serum. This decrease in IL-6 may promote microglial proliferation and survival as a modulatory effect response, while the increase in BDNF might suggest a regulatory mechanism in microglia–neuron interaction responses. However, tDCS did not enhance the cognitive or modulatory effects of CS, suggesting that longer interventions might be required to achieve substantial benefits.

Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2′ 3′-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin’s beneficial effects for counteracting temozolomide’s side effects.