Diabetes-Alzheimer's connection in older age: SGLT2 inhibitors as promising modulators of disease pathways.

Late-onset Alzheimer's disease (LOAD) is the most frequent cause of dementia in older persons. Subjects affected by type 2 diabetes mellitus (T2DM) are at higher risk of vascular disease, cognitive decline, and dementia. LOAD has many characteristics shared with impaired insulin signaling pathways, and substantial evidence has demonstrated a pivotal role in dysregulated glucose metabolism in its pathogenesis. Recent studies have shown that some anti-diabetic drugs, other than regulating the metabolism of peripheral tissues, can also modulate the brain's metabolism, reduce inflammation, and have a direct neuroprotective effect. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are a newer class with many pleiotropic effects that may have strong neuroprotective potential. After a summary of the principal "anti-diabetic" drugs acting as suitable candidates in treating LOAD, this narrative review explored the potential role of SGLT2i on cognition from pre-clinical to clinical studies.

A blast from the past: To tame time with metformin.

The strong evidence of metformin use in subjects affected by type 2 diabetes (T2DM) on health outcomes, together with data from pre-clinical studies, has led the gerontological research to study the therapeutic potential of such a drug as a slow-aging strategy. However, despite clinical use for over fifty years as an anti-diabetic drug, the mechanisms of action beyond glycemic control remain unclear. In this review, we have deeply examined the literature, doing a narrative review from the metformin story, through mechanisms of action to slow down aging potential, from lower organisms to humans. Based on the available evidence, we conclude that metformin, as shown in lower organisms and mice, may be effective in humans' longevity. A complete analysis and follow-up of ongoing clinical trials may provide more definitive answers as to whether metformin should be promoted beyond its use to treat T2DM as a drug that enhances both healthspan and lifespan.

Inverse correlation between plasma 2-arachidonoylglycerol levels and subjective severity of depression.

OBJECTIVE: Endocannabinoids have been implicated in the pathophysiology of Major Depressive Disorder (MDD) and might represent potential targets for therapeutic intervention. Objectives of the study were: (1) to measure plasma levels of endocannabinoids in a group of antidepressant-free depressed outpatients; (2) to explore their relationship with the severity of depressive symptoms as subjectively perceived by the patients; and (3) to investigate the effect of the selective serotonin reuptake inhibitor escitalopram on endocannabinoid levels. METHODS: We measured plasma levels of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anadamide), in 12 drug-free outpatients diagnosed with MDD and in 12 matched healthy controls. In the patient group, endocannabinoids plasma levels were assessed at baseline and after 2 months of treatment with escitalopram. RESULTS: Baseline plasma levels of the two endocannabinoids did not differ between depressed patients and healthy controls. However, there was a significant inverse correlation between 2-arachidonoylglycerol levels and the severity of subjectively perceived depressive symptoms. Treatment with escitalopram did not change endocannabinoid levels in depressed patients, although it caused the expected improvement of depressive symptoms. CONCLUSIONS: Our results suggest that 2-arachidonylglycerol, the most abundant endocannabinoid in the central nervous system, might act to mitigate depressive symptoms, and raise the interesting possibility that 2-arachidonylglycerol and anandamide are differentially regulated in patients affected by MDD. Also, our data suggest but do not prove that the endocannabinoid system is not regulated by serotonergic transmission, at least in depressed patients.

Loss of TrkB Signaling in Parvalbumin-Expressing Basket Cells Results in Network Activity Disruption and Abnormal Behavior.

The GABAergic system is regulated by the brain-derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) pathway, but the cell-intrinsic role of TrkB signaling in parvalbumin cortical interneuron development and function is unclear. We performed conditional ablation of the TrkB receptor in parvalbumin-expressing (PV) interneurons to study whether postnatal loss of TrkB in parvalbumin cells affects their survival, connectivity, spontaneous and evoked neuronal activity and behavior. Using in vivo recordings of local field potentials, we found reduced gamma oscillations in the sensory cortex of PVcre+; TrkBF/F conditional knockout mice (TrkB cKO), along with increased firing of putative excitatory neurons. There was a significant downregulation in parvalbumin neuron number in cerebral and cerebellar cortices of TrkB cKO mice. In addition, inhibitory synaptic connections between basket cells and pyramidal neurons were profoundly reduced in the neocortex of TrkB cKO mice and there was a loss of cortical volume. TrkB cKO mice also showed profound hyperactivity, stereotypies, motor deficits and learning/memory defects. Our findings demonstrate that the targeting and/or synapse formation of PV-expressing basket cells with principal excitatory neurons require TrkB signaling in parvalbumin cells. Disruption of this signaling has major consequences for parvalbumin interneuron connectivity, network dynamics, cognitive and motor behavior.

Effects of escitalopram on serum BDNF levels in elderly patients with depression: a preliminary report.

BACKGROUND AND AIMS: Increasing evidence in the literature suggests a link between the brain-derived neurotrophic factor (BDNF) system and adult depression, supporting a role in the pathophysiology of the disease and response to therapy. Few studies have reported BDNF serum levels in elderly depressed subjects and their relationship with antidepressant therapy. The aim of the study was to evaluate BDNF serum levels in naive elderly depressed patients, before and after antidepressant treatment. METHODS: We enrolled n = 5 elderly naive patients affected by depression, according to the Diagnostic and Statistical Manual of Mental Disorders-IV Text Revision criteria for major depressive episode. BDNF serum levels were evaluated through ELISA method. Cognitive functions were examined by Mini Mental State Examination (MMSE) and severity of depression was assessed by Geriatric Depression Scale (GDS). BDNF levels were measured at baseline (T0) and after 2 months (T2) of escitalopram. Ten healthy elderly subjects were enrolled as a control group. RESULTS: The serum BDNF levels in patients (T0) and controls were 11.5 ± 0.6 and 13.6 ± 3.4 ng/ml (m ± SD), respectively. At T2, the patients showed a significant improvement of depressive symptoms (p < 0.05), with a not significant increase of MMSE. The serum BDNF concentrations increased to 16.0 ± 2.7 ng/ml at T2 (p < 0.05), beyond the levels of BDNF in controls. The increase in BDNF levels was significantly related to the improvement in GDS scores of the patients (r = 0.9, p < 0.05). CONCLUSIONS: Serum BDNF levels may be considered as a marker of response to antidepressant treatment for depression in the elderly.

Hypoxia-induced developmental delays of inhibitory interneurons are reversed by environmental enrichment in the postnatal mouse forebrain.

Infants born premature experience hypoxic episodes due to immaturity of their respiratory and central nervous systems. This profoundly affects brain development and results in cognitive impairments. We used a mouse model to examine the impact of hypoxic rearing (9.5-10.5% O2) from postnatal day 3 to 11 (P3-P11) on GABAergic interneurons and the potential for environmental enrichment to ameliorate these developmental abnormalities. At P15 the numbers of cortical interneurons expressing immunohistochemically detectable levels of parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide were decreased in hypoxic-reared mice by 59%, 32%, and 38%, respectively, compared with normoxic controls. Hypoxia also decreased total GABA content in frontal neocortex by 31%. However, GAD67-EGFP knock-in mice reared under hypoxic conditions showed no changes in total number of GAD67-EGFP(+) cells and no evidence of increased interneuron death, suggesting that the total number of interneurons was not decreased, but rather, that hypoxic-rearing decreased interneuron marker expression in these cells. In adulthood, PV and SST expression levels were decreased in hypoxic-reared mice. In contrast, intensity of reelin (RLN) expression was significantly increased in adult hypoxic-reared mice compared with normoxic controls. Housing mice in an enriched environment from P21 until adulthood normalized phenotypic interneuron marker expression without affecting total interneuron numbers or leading to increased neurogenesis. Our data show that (1) hypoxia decreases PV and SST and increases RLN expression in cortical interneurons during postnatal cortical development and (2) enriched environment has the capacity to normalize the interneuron abnormalities in cortex.

L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors.

Epigenetic mechanisms are involved in the pathophysiology of depressive disorders and are unique potential targets for therapeutic intervention. The acetylating agent L-acetylcarnitine (LAC), a well-tolerated drug, behaves as an antidepressant by the epigenetic regulation of type 2 metabotropic glutamate (mGlu2) receptors. It caused a rapid and long-lasting antidepressant effect in Flinders Sensitive Line rats and in mice exposed to chronic unpredictable stress, which, respectively, model genetic and environmentally induced depression. In both models, LAC increased levels of acetylated H3K27 bound to the Grm2 promoter and also increased acetylation of NF-ĸB-p65 subunit, thereby enhancing the transcription of Grm2 gene encoding for the mGlu2 receptor in hippocampus and prefrontal cortex. Importantly, LAC reduced the immobility time in the forced swim test and increased sucrose preference as early as 3 d of treatment, whereas 14 d of treatment were needed for the antidepressant effect of chlorimipramine. Moreover, there was no tolerance to the action of LAC, and the antidepressant effect was still seen 2 wk after drug withdrawal. Conversely, NF-ĸB inhibition prevented the increase in mGlu2 expression induced by LAC, whereas the use of a histone deacetylase inhibitor supported the epigenetic control of mGlu2 expression. Finally, LAC had no effect on mGlu2 knockout mice exposed to chronic unpredictable stress, and a single injection of the mGlu2/3 receptor antagonist LY341495 partially blocked LAC action. The rapid and long-lasting antidepressant action of LAC strongly suggests a unique approach to examine the epigenetic hypothesis of depressive disorders in humans, paving the way for more efficient antidepressants with faster onset of action.