Chloroquine Restores Ganglioside Homeostasis and Improves Pathological and Behavioral Outcomes Post-stroke in the Rat

Abstract

Perturbations of ganglioside homeostasis have been observed following stroke whereby toxic simple gangliosides GM2 and GM3 accumulate, while protective complex species GM1 and GD1 are reduced. Thus, there is a need for therapeutic interventions which can prevent ganglioside dysregulation after stroke. A pharmacological intervention using chloroquine was selected for its transient lysosomotropic properties which disrupt the activity of catabolic ganglioside enzymes. Chloroquine was administered both in vitro (0.1 μM), to primary cortical neurons exposed to GM3 toxicity, and in vivo (45 mg/kg i.p.), to 3-month-old male Wistar rats that underwent a severe stroke injury. Chloroquine was administered for seven consecutive days beginning 3 days prior to the stroke injury. Gangliosides were examined using MALDI imaging mass spectrometry at 3 and 21 days after the injury, and motor deficits were examined using the ladder task. Chloroquine treatment prevented ganglioside dysregulation 3 days post-stroke and partially prevented complex ganglioside depletion 21 days post-stroke. Exogenous GM3 was found to be toxic to primary cortical neurons which was protected by chloroquine treatment. Motor deficits were prevented in the forelimbs of stroke-injured rats with chloroquine treatment and was associated with decreased inflammation, neurodegeneration, and an increase in cell survival at the site of injury. Chloroquine administration prevents ganglioside dysregulation acutely, protects against GM3 toxicity in neurons, and is associated with long-term functional and pathological improvements after stroke in the rat. Therefore, targeting lipid dysregulation using lysosomotropic agents such as chloroquine may represent a novel therapeutic avenue for stroke injuries.

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

“…The authors of this study proposed that the shift from complex to simple gangliosides might be due to the catabolism of complex gangliosides with accumulation of deriving GM2 and GM3 in the lysosomes (Whitehead et al, 2011). In support of this hypothesis, administration of chloroquine in rats, prior to and after stroke, to block ganglioside catabolism, prevented the shift from complex to simple gangliosides as well as motor deficits, decreased inflammation and increased cell survival at the injury site (Caughlin et al, 2019). These data suggest that the depletion of complex gangliosides due to their catabolism might contribute to tissue damage in stroke models and that increasing endogenous ganglioside synthesis might have beneficial effects.…”

Chloroquine Protects Hypoxia/Ischemia-Induced Neonatal Brain Injury in Rats by Mitigating Blood–Brain Barrier Disruption

“…2,22 CQ is best known as an antimalarial drug, which has been demonstrated to have good application value and therapeutic potential in various animal models of neurological disorders. [12][13][14]23 Furthermore, no obvious adverse events or reproductive toxicity were found after CQ intervention in the animal experiments and clinical patients. 11 Herein, to some extent, we believe that CQ will be a safe therapeutic option for HIBD in neonates due to its peculiarity of low toxicity and well-tolerated therapy.…”

“…Second, CQ had been identified to protect BBB integrity and prevent neuronal cell death in newborn rats after HIBD. Interestingly, CQ possessed anti-inflammatory properties in CNS diseases, , and whether or not CQ treatment protects the neurovascular unit (NVU) in neonatal HIBD by regulating neuroinflammation should be further studied. Furthermore, hypothermia is already considered as the standard therapy for neonatal hypoxic-ischemic encephalopathy (HIE), but it is not universally successful .…”

“…Chloroquine (CQ), a widely used antimalarial and antirheumatoid agent, has been shown to exhibit good safety in a clinical setting . In multiple studies, CQ has been precisely proved to confer beneficial effects on experimentally induced neurological diseases such as traumatic brain injury, cerebral ischemia, Parkinson’s disease, and other neurodegenerative diseases. − Increasing studies have demonstrated that CQ exerts neuroprotective effects through broad actions, including suppression of inflammation, amelioration of oxidation, reduction of neuronal death, and protection of the BBB. ,,, However, to date, few studies have addressed the beneficial role of CQ in a neonatal rat model of HIBD, and less is known about the underlying mechanisms. In the present study, the Rice–Vannucci rat model was chosen to provoke HIBD, and we test the hypothesis that CQ treatment could reduce HIBD via stabilizing the BBB.…”

Expression pattern and clinical value of Key RNA methylation modification regulators in ischemic stroke

“…Chloroquine, an established drug originally used for the treatment of malaria, has been reported to have anti-inflammatory and immunomodulatory properties ( Silva et al, 2021 ). Recently, several studies have shown that chloroquine pretreatment can alleviate brain injury in IS through a variety of mechanisms, including the inhibition of the inflammatory response by lowering myeloperoxidase activity and inflammatory cytokine gene expression ( Cui et al, 2013 ; Zhang Y. P. et al, 2020 ) and alleviation of neuronal injury by restoring ganglioside homeostasis ( Caughlin et al, 2019 ). Gabriel et al (2014) reported that chloroquine can effectively increase Gpnmb transcription in mice as a lysosomal stress inducer.…”