Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice

Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change – increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7–21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type–specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.

Visual hallucination caused by multiloculated hydrocephalus in the frontal lobe: a case report

A 72-year-old man consulted our hospital for visual hallucination. His non-contrast computed tomography (CT) of head showed multiloculated hydrocephalus in the frontal lobe. Memantine treatment was started and his visual hallucination disappeared. This is a rare case of frontal lobe damage causing visual hallucination.

Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct

Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

Effect of Memantine Treatment and Combination with Vitamin D Supplementation on Body Composition in the APP/PS1 Mouse Model of Alzheimer’s Disease Following Chronic Vitamin D Deficiency

Background: Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n = 14), while the other had both memantine and 10 IU/g vitamin D (n = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p < 0.01) and absolute skeletal tissue mass (9.3% increase, p < 0.05) and volume (9.2% increase, p < 0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.

Cortical Stroke Produces Secondary Injury and Long-lasting Gliosis in the Ipsilateral Thalamus

Remote secondary injury in the thalamus has been observed following cortical infarct, however the mechanisms are not well understood. We used the distal MCAO stroke model (pdMCAO) to explore the cellular and temporal gliosis response in secondary thalamic injury in mice. At 3 days post-stroke (PSD3), primary infarct was limited to the cortex, with no infarct in the thalamus. However, at 2 weeks after stroke (PSD14), the ipsilateral thalamus demonstrated degenerating and severely damaged neurons. Staining for GFAP (astrogliosis) or IBA-1 (microgliosis) was first apparent in the ipsilateral thalamus by PSD3, and showed a progressive increase through PSD14. The number of activated microglia was increased within the thalamus at PSD14, reflecting proliferation of resident microglia as well as infiltration of peripheral monocytes. Interestingly, astrogliosis within the thalamus was enduring, as it was still evident at two years post-stroke. Furthermore, the astrogliosis at two years (but not at 6 weeks) demonstrated glial scar-like characteristics. Lastly, we demonstrated that post-stroke treatment with an NMDA receptor antagonist (memantine) reduces gliosis in the thalamus at PSD14. These findings highlight the development of lasting secondary injury in the thalamus following cortical stroke and support the value of memantine treatment in the mitigation of this injury.

Cortical stroke produces secondary injury and long-lasting gliosis in the ipsilateral thalamus

Remote secondary injury in the thalamus has been observed following cortical infarct, however the mechanisms are not well understood. We used the distal MCAO stroke model (pdMCAO) to explore the cellular and temporal gliosis response in secondary thalamic injury in mice. At 3 days post-stroke (PSD3), primary infarct was limited to the cortex, with no infarct in the thalamus. However, at 2 weeks after stroke (PSD14), the ipsilateral thalamus demonstrated degenerating and severely damaged neurons. Staining for GFAP (astrogliosis) or IBA-1 (microgliosis) was first apparent in the ipsilateral thalamus by PSD3, and showed a progressive increase through PSD14. The number of activated microglia was increased within the thalamus at PSD14, reflecting proliferation of resident microglia as well as infiltration of peripheral monocytes. Interestingly, astrogliosis within the thalamus was enduring, as it was still evident at two years post-stroke. Furthermore, the astrogliosis at two years (but not at 6 weeks) demonstrated glial scar-like characteristics. Lastly, we demonstrated that post-stroke treatment with an NMDA receptor antagonist (memantine) reduces gliosis in the thalamus at PSD14. These findings highlight the development of lasting secondary injury in the thalamus following cortical stroke and support the value of memantine treatment in the mitigation of this injury.

Antitumorigenic Effect of Memantine via Interfering Glutamate Metabolism in Mouse 4T1 Breast Tumor Model

Background: Repurposing drugs is an efficient strategy as drug discovery process is time-consuming, laborious and costly. Memantine is already used in Alzheimer’s disease to prevent neurons from excess glutamate toxicity. As cancer cells benefit higher amounts of cellular energetics like glucose and glutamine, we used memantine to interfere with the glutamate metabolism in order to restrict cancer cells glutamine as a source for their growth. Objective: To investigate the potential antitumor effect of memantine by reducing glutamate levels in 4T1 mouse breast cancer model. Methods: 24 Balb/c female mice were subcutaneously inoculated with 4T1 cells. When tumors were palpable memantine treatment was initiated as 5 and 10 mg/kg daily intraperitoneal injection. Tumor growth was recorded for every 2–3 days. Tumor volumes, serum glutamate levels, spleen IL-6 levels, genome-wide DNA methylation levels and GSK3B. pGSK3B protein expressions were measured to enlighten the anticancer mechanism of action for memantine. Results: We found that both two doses (5 and 10mg/kg) decreased tumor growth rates and serum glutamate levels significantly (p<0.05). 10mg/kg treatment increased spleen IL-6 levels (p<0.05) and decreased genome-wide DNA methylation levels. Memantine treatment decreased GSK3B protein expression levels in tumor tissue samples. Conclusion: To the best of our knowledge this is the first study that investigates the antitumor activity of memantine in breast cancer tumor model. Our results suggest a potent anticancer mechanism of action for memantine. Memantine decreased genome wide methylation and serum glutamate levels that are associated with a poor prognosis. Therefore, Memantine might be used for targeting glutamine metabolism in cancer treatment.