scholarly journals Animal models of chemotherapy-induced cognitive decline in preclinical drug development

2021 ◽  
Author(s):  
Jeena John ◽  
Manas Kinra ◽  
Jayesh Mudgal ◽  
G. L. Viswanatha ◽  
K. Nandakumar
Keyword(s):  
Animal Models ◽  
Human Cancer ◽  
Critical Evaluation ◽  
Significant Risk ◽  
Long Term Potentiation ◽  
Chemotherapeutic Agents ◽  
Therapeutic Interventions ◽  
Cognitive Changes ◽  
Tumor Bearing

Abstract Rationale Chemotherapy-induced cognitive impairment (CICI), chemobrain, and chemofog are the common terms for mental dysfunction in a cancer patient/survivor under the influence of chemotherapeutics. CICI is manifested as short/long term memory problems and delayed mental processing, which interferes with a person’s day-to-day activities. Understanding CICI mechanisms help in developing therapeutic interventions that may alleviate the disease condition. Animal models facilitate critical evaluation to elucidate the underlying mechanisms and form an integral part of verifying different treatment hypotheses and strategies. Objectives A methodical evaluation of scientific literature is required to understand cognitive changes associated with the use of chemotherapeutic agents in different preclinical studies. This review mainly emphasizes animal models developed with various chemotherapeutic agents individually and in combination, with their proposed mechanisms contributing to the cognitive dysfunction. This review also points toward the analysis of chemobrain in healthy animals to understand the mechanism of interventions in absence of tumor and in tumor-bearing animals to mimic human cancer conditions to screen potential drug candidates against chemobrain. Results Substantial memory deficit as a result of commonly used chemotherapeutic agents was evidenced in healthy and tumor-bearing animals. Spatial and episodic cognitive impairments, alterations in neurotrophins, oxidative and inflammatory markers, and changes in long-term potentiation were commonly observed changes in different animal models irrespective of the chemotherapeutic agent. Conclusion Dyscognition exists as one of the serious side effects of cancer chemotherapy. Due to differing mechanisms of chemotherapeutic agents with differing tendencies to alter behavioral and biochemical parameters, chemotherapy may present a significant risk in resulting memory impairments in healthy as well as tumor-bearing animals.

scholarly journals Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9318
Author(s):  
Sofia Toniolo ◽  
Arjune Sen ◽  
Masud Husain
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Viral Vectors ◽  
Epileptiform Activity ◽  
Long Term Potentiation ◽  
Therapeutic Interventions ◽  
Epileptiform Discharges ◽  
Aβ Amyloid ◽  
Brain Hyperexcitability

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology.

scholarly journals Long-Term Potentiation and Memory

2004 ◽  
Vol 84 (1) ◽  
pp. 87-136 ◽  
Author(s):  
M. A. LYNCH
Keyword(s):  
Animal Models ◽  
Cell Signaling ◽  
Spatial Learning ◽  
Gene Knockout ◽  
Transgenic Animals ◽  
Long Term Potentiation ◽  
Afferent Pathways ◽  
Term Potentiation ◽  
Signaling Events

Lynch, MA. Long-Term Potentiation and Memory. Physiol Rev 84: 87–136, 2004; 10.1152/physrev.00014.2003.—One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.

scholarly journals Hormones and the hippocampus

2001 ◽  
Vol 169 (2) ◽  
pp. 205-231 ◽  
Author(s):  
R Lathe
Keyword(s):  
Blood Pressure ◽  
Reproductive Function ◽  
Long Term Potentiation ◽  
Cognitive Changes ◽  
Physiological Regulation ◽  
Term Potentiation ◽  
Exact Function ◽  
Hippocampal Lesions

Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure. Evidence is presented that its role in memory may be ancillary to physiological regulation. Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress. Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes. This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception'). Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function. It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli. Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (e.g. long-term potentiation) could facilitate throughput inhibition. This may have implications for the role of the hippocampus and long-term potentiation in memory.

scholarly journals Long-term use of antidepressants, mood stabilizers, and antipsychotics in pediatric patients with a focus on appropriate deprescribing

2021 ◽  
Vol 11 (6) ◽  
pp. 320-333
Author(s):  
Danielle L. Stutzman
Keyword(s):  
Critical Evaluation ◽  
Significant Risk ◽  
Child And Adolescent Psychiatry ◽  
Psychotropic Medications ◽  
Mood Stabilizers ◽  
Supporting Evidence ◽  
Social Changes ◽  
Treatment Facilities

Abstract It is estimated that 8% to 12% of youth are prescribed psychotropic medications. Those in foster care, juvenile justice systems, residential treatment facilities, and with developmental or intellectual disabilities are more likely to be prescribed high-risk regimens. The use of psychotropic medications in this age group is often off-label and can be associated with significant risk, warranting critical evaluation of their role. Landmark trials, pediatric-specific guidelines, and state-driven initiatives play critical roles in supporting evidence-based use of psychotropic medications in children. Overall, there is a lack of literature describing the long-term use of psychotropic medications in youth—particularly with regard to neurobiological, physical, and social changes that occur throughout development. Deprescribing is an important practice in child and adolescent psychiatry, given concerns for over-prescribing, inappropriate polytherapy, and the importance of reevaluating the role of psychotropic medications as children develop.

scholarly journals Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

2019 ◽  
Author(s):  
Cleiton Lopes-Aguiar ◽  
Rafael N. Ruggiero ◽  
Matheus T. Rossignoli ◽  
Ingrid de Miranda Esteves ◽  
José Eduardo Peixoto Santos ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Synaptic Plasticity ◽  
Animal Models ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
High Frequency Stimulation ◽  
Evoked Responses ◽  
Term Potentiation

ABSTRACTN-methyl-D-aspartate receptor (NMDAr) antagonists such as ketamine (KET) produce psychotic-like behavior in both humans and animal models. NMDAr hypofunction affects normal oscillatory dynamics and synaptic plasticity in key brain regions related with schizophrenia, particularly in the hippocampus and the prefrontal cortex. In contrast, long-term potentiation (LTP) induction is known to increase glutamatergic transmission. Thus, we hypothesized that LTP could mitigate the electrophysiological changes promoted by KET. We recorded HPC-PFC local field potentials and evoked responses in urethane anesthetized rats, before and after KET administration, preceded or not by LTP induction. Our results show that KET promotes an aberrant delta-high-gamma crossfrequency coupling in the PFC and an enhancement in HPC-PFC evoked responses. LTP induction prior to KET attenuates changes in synaptic efficiency and prevents the increase in cortical gamma amplitude comodulation. These findings are consistent with evidence that increased efficiency of glutamatergic receptors attenuates cognitive impairment in animal models of psychosis. Therefore, high-frequency stimulation in HPC may be a useful tool to better understand how to prevent NMDAr hypofunction effects on synaptic plasticity and oscillatory coordination in cortico-limbic circuits.

scholarly journals Repeated Mild Traumatic Brain Injury Causes Chronic Neuroinflammation, Changes in Hippocampal Synaptic Plasticity, and Associated Cognitive Deficits

2014 ◽  
Vol 34 (7) ◽  
pp. 1223-1232 ◽  
Author(s):  
Stephanie L Aungst ◽  
Shruti V Kabadi ◽  
Scott M Thompson ◽  
Bogdan A Stoica ◽  
Alan I Faden
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Hippocampal Slices ◽  
Neuronal Cell ◽  
Long Term Potentiation ◽  
Cognitive Changes ◽  
Chronic Neuroinflammation ◽  
Term Potentiation

Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration.

scholarly journals Natural history observations in moderate aortic stenosis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yu Du ◽  
Mario Gössl ◽  
Santiago Garcia ◽  
Maurice Enriquez-Sarano ◽  
Joao L. Cavalcante ◽  
...  
Keyword(s):  
Overall Survival ◽  
Natural History ◽  
Aortic Stenosis ◽  
Nyha Class ◽  
Significant Risk ◽  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Term Survival ◽  
Risk Of Death

Abstract Background The natural history of patients with moderate aortic stenosis (AS) is poorly understood. We aimed to determine the long-term outcomes of patients with moderate AS. Methods We examined patients with moderate AS defined by echocardiography in our healthcare system, and performed survival analyses for occurrence of death, heart failure (HF) hospitalization, and progression of AS, with accounting for symptoms, left ventricular dysfunction, and comorbidities. Results We examined 729 patients with moderate AS (median age, 76 years; 59.9 % men) with a median follow-up of 5.0 years (interquartile range: 2.0 to 8.1 years). The 5-year overall survival was 52.3 % (95 % confidence interval [CI]: 48.6 % to 56.0 %) and survival free of death or HF hospitalization was 43.2 % (95 % CI: 39.5 % to 46.9 %). Worse New York Heart Association (NYHA) functional class was associated with poor long-term survival, with mortality rates ranging from 7.9 % (95 % CI: 6.6–9.2 %) to 25.2 % (95 % CI: 20.2–30.3 %) per year. Among patients with minimal or no symptoms, no futility markers, and preserved left ventricular function, 5-year overall survival was 71.9 % (95 % CI: 66.4–77.4 %) and survival free of death or HF hospitalization was 61.4 % (95 % CI: 55.5–67.3 %). Risk factors associated with adverse events were age, NYHA class, low ejection fraction and high aortic valve velocity (all p < 0.05). Conclusions Patients with moderate AS are at significant risk of death. Our findings highlight the need for more study into appropriate therapeutic interventions to improve the prognosis of these patients.

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