Lack of Autophagy Induction by Lithium Decreases Neuroprotective Effects in the Striatum of Aged Rats

Abstract

The pharmacological modulation of autophagy is considered a promising neuroprotective strategy. While it has been postulated that lithium regulates this cellular process, the age-related effects have not been fully elucidated. Here, we evaluated lithium-mediated neuroprotective effects in young and aged striatum. After determining the optimal experimental conditions for inducing autophagy in loco with lithium carbonate (Li2CO3), we measured cell viability, reactive oxygen species (ROS) generation and oxygen consumption with rat brain striatal slices from young and aged animals. In the young striatum, Li2CO3 increased tissue viability and decreased ROS generation. These positive effects were accompanied by enhanced levels of LC3-II, LAMP 1, Ambra 1 and Beclin-1 expression. In the aged striatum, Li2CO3 reduced the autophagic flux and increased the basal oxygen consumption rate. Ultrastructural changes in the striatum of aged rats that consumed Li2CO3 for 30 days included electrondense mitochondria with disarranged cristae and reduced normal mitochondria and lysosomes area. Our data show that the striatum from younger animals benefits from lithium-mediated neuroprotection, while the striatum of older rats does not. These findings should be considered when developing neuroprotective strategies involving the induction of autophagy in aging.

Does treatment with autophagy-enhancers and/or ROS-scavengers alleviate behavioral and neurochemical consequences of low-dose rotenone-induced mild mitochondrial dysfunction in mice?

“…Rapamycin, resveratrol, NAC and Mn-Tbap counteracted most of rotenone’s effects on OCR-parameters only after 72 h [ 11 ], possibly via different mechanisms, not necessarily related to their autophagy enhancement and/or ROS scavenging effects. Lithium-induced reversal of rotenone on OCR-parameters is compatible with the drug’s known positive effects on mitochondrial-function [ 75 – 77 ], possibly mediated via its effect on autophagy/mitophagy [ 75 , 78 ]. Indeed, Osete et al [ 76 ] recently reported amelioration of rotenone-induced mitochondrial respiration malfunction (measured as OCR) in iPSCs (induced pluripotent stem cells) derived neural precursor cells by lithium.…”

An Overview of the Neurotrophic and Neuroprotective Properties of the Psychoactive Drug Lithium as an Autophagy Modulator in Neurodegenerative Conditions

“…However, Li 2 CO 3 increased basal oxygen consumption and decreased autophagic flow in the elderly striatum. Aged rats' striatums showed ultrastructural alterations, including lower amounts of normal mitochondria and lysosomes and electro-dense mitochondria with disorganized cristae [ 42 ]. As a result, the data indicate that, whereas older rats do not benefit from lithium-mediated neuroprotection, younger animals do.…”