Muhammad Asim

All Publications

• Unraveling the Role of Cholecystokinin in Epilepsy: Mechanistic Insight Into Neuroplasticity. Neurochemistry international Asim, M., Qianqian, G., Waris, A., Wang, H., Lai, Y., Chen, X. 2024: 105870

  Abstract

  Epilepsy is a disorder characterized by an imbalance between excitability and inhibition, leading to uncontrolled hyperexcitability of neurons in the central nervous system. Despite the prevalence of epileptic seizures, the underlying mechanisms driving this hyperexcitability remain poorly understood. This review article aims to enhance our understanding of the mechanisms of epilepsy, with a specific focus on the role of cholecystokinin (CCK) in this debilitating disease. We will begin with an introduction to the topic, followed by an examination of the role of GABAergic neurons and the synaptic plasticity mechanisms associated with seizures. As we delve deeper, we will elucidate how CCK and its receptors contribute to seizure behavior. Finally, we will discuss the CCK-dependent synaptic plasticity mechanisms and highlight their potential implications in seizure activity. Through a comprehensive examination of these aspects, this review provides valuable insights into the involvement of CCK and its receptors in epilepsy. By improving our understanding of the mechanisms underlying this condition, particularly the role of CCK, we aim to contribute to the development of more effective treatment strategies.

  View details for DOI 10.1016/j.neuint.2024.105870

  View details for PubMedID 39343303

• Cholecystokinin neurotransmission in the central nervous system: Insights into its role in health and disease. BioFactors (Oxford, England) Asim, M., Wang, H., Waris, A., Qianqian, G., Chen, X. 2024

  Abstract

  Cholecystokinin (CCK) plays a key role in various brain functions, including both health and disease states. Despite the extensive research conducted on CCK, there remain several important questions regarding its specific role in the brain. As a result, the existing body of literature on the subject is complex and sometimes conflicting. The primary objective of this review article is to provide a comprehensive overview of recent advancements in understanding the central nervous system role of CCK, with a specific emphasis on elucidating CCK's mechanisms for neuroplasticity, exploring its interactions with other neurotransmitters, and discussing its significant involvement in neurological disorders. Studies demonstrate that CCK mediates both inhibitory long-term potentiation (iLTP) and excitatory long-term potentiation (eLTP) in the brain. Activation of the GPR173 receptor could facilitate iLTP, while the Cholecystokinin B receptor (CCKBR) facilitates eLTP. CCK receptors' expression on different neurons regulates activity, neurotransmitter release, and plasticity, emphasizing CCK's role in modulating brain function. Furthermore, CCK plays a pivotal role in modulating emotional states, Alzheimer's disease, addiction, schizophrenia, and epileptic conditions. Targeting CCK cell types and circuits holds promise as a therapeutic strategy for alleviating these brain disorders.

  View details for DOI 10.1002/biof.2081

  View details for PubMedID 38777339

• Shedding light on cholecystokinin's role in hippocampal neuroplasticity and memory formation. Neuroscience and biobehavioral reviews Asim, M., Wang, H., Chen, X. 2024; 159: 105615

  Abstract

  The hippocampus is a crucial brain region involved in the process of forming and consolidating memories. Memories are consolidated in the brain through synaptic plasticity, and a key mechanism underlying this process is called long-term potentiation (LTP). Recent research has shown that cholecystokinin (CCK) plays a role in facilitating the formation of LTP, as well as learning and memory consolidation. However, the specific mechanisms by which CCK is involved in hippocampal neuroplasticity and memory formation are complicated or poorly understood. This literature review aims to explore the role of LTP in memory formation, particularly in relation to hippocampal memory, and to discuss the implications of CCK and its receptors in the formation of hippocampal memories. Additionally, we will examine the circuitry of CCK in the hippocampus and propose potential CCK-dependent mechanisms of synaptic plasticity that contribute to memory formation.

  View details for DOI 10.1016/j.neubiorev.2024.105615

  View details for PubMedID 38437975

• Potentiated GABAergic neuronal activities in the basolateral amygdala alleviate stress-induced depressive behaviors. CNS neuroscience & therapeutics Asim, M., Wang, H., Chen, X., He, J. 2024; 30 (3): e14422

  Abstract

  Major depressive disorder is a severe psychiatric disorder that afflicts ~17% of the world population. Neuroimaging investigations of depressed patients have consistently reported the dysfunction of the basolateral amygdala in the pathophysiology of depression. However, how the BLA and related circuits are implicated in the pathogenesis of depression is poorly understood.Here, we combined fiber photometry, immediate early gene expression (c-fos), optogenetics, chemogenetics, behavioral analysis, and viral tracing techniques to provide multiple lines of evidence of how the BLA neurons mediate depressive-like behavior.We demonstrated that the aversive stimuli elevated the neuronal activity of the excitatory BLA neurons (BLACAMKII neurons). Optogenetic activation of CAMKII neurons facilitates the induction of depressive-like behavior while inhibition of these neurons alleviates the depressive-like behavior. Next, we found that the chemogenetic inhibition of GABAergic neurons in the BLA (BLAGABA ) increased the firing frequency of CAMKII neurons and mediates the depressive-like phenotypes. Finally, through fiber photometry recording and chemogenetic manipulation, we proved that the activation of BLAGABA neurons inhibits BLACAMKII neuronal activity and alleviates depressive-like behavior in the mice.Thus, through evaluating BLAGABA and BLACAMKII neurons by distinct interaction, the BLA regulates depressive-like behavior.

  View details for DOI 10.1111/cns.14422

  View details for PubMedID 37715582

  View details for PubMedCentralID PMC10915993

• Cholecystokinin B receptor antagonists for the treatment of depression via blocking long-term potentiation in the basolateral amygdala. Molecular psychiatry Zhang, X., Asim, M., Fang, W., Md Monir, H., Wang, H., Kim, K., Feng, H., Wang, S., Gao, Q., Lai, Y., He, J. 2023

  Abstract

  Depression is a common and severe mental disorder. Evidence suggested a substantial causal relationship between stressful life events and the onset of episodes of major depression. However, the stress-induced pathogenesis of depression and the related neural circuitry is poorly understood. Here, we investigated how cholecystokinin (CCK) and CCKBR in the basolateral amygdala (BLA) are implicated in stress-mediated depressive-like behavior. The BLA mediates emotional memories, and long-term potentiation (LTP) is widely considered a trace of memory. We identified that the cholecystokinin knockout (CCK-KO) mice impaired LTP in the BLA, while the application of CCK4 induced LTP after low-frequency stimulation (LFS). The entorhinal cortex (EC) CCK neurons project to the BLA and optogenetic activation of EC CCK afferents to BLA-promoted stress susceptibility through the release of CCK. We demonstrated that EC CCK neurons innervate CCKBR cells in the BLA and CCK-B receptor knockout (CCKBR-KO) mice impaired LTP in the BLA. Moreover, the CCKBR antagonists also blocked high-frequency stimulation (HFS) induced LTP formation in the BLA. Notably, CCKBR antagonists infusion into the BLA displayed an antidepressant-like effect in the chronic social defeat stress model. Together, these results indicate that CCKBR could be a potential target to treat depression.

  View details for DOI 10.1038/s41380-023-02127-7

  View details for PubMedID 37365241

  View details for PubMedCentralID 8813060

• Altered neurotransmission in stress-induced depressive disorders: The underlying role of the amygdala in depression. Neuropeptides Asim, M., Wang, H., Waris, A. 2023; 98: 102322

  Abstract

  Depression is the second leading cause of disability in the world population, for which currently available pharmacological therapies either have poor efficacy or have some adverse effects. Accumulating evidence from clinical and preclinical studies demonstrates that the amygdala is critically implicated in depressive disorders, though the underlying pathogenesis mechanism needs further investigation. In this literature review, we overviewed depression and the key role of Gamma-aminobutyric acid (GABA) and Glutamate neurotransmission in depression. Notably, we discussed a new cholecystokinin-dependent plastic changes mechanism under stress and a possible antidepressant response of cholecystokinin B receptor (CCKBR) antagonist. Moreover, we discussed the fundamental role of the amygdala in depression, to discuss and understand the pathophysiology of depression and the inclusive role of the amygdala in this devastating disorder.

  View details for DOI 10.1016/j.npep.2023.102322

  View details for PubMedID 36702033

• Ketamine attenuates the PTSD-like effect via regulation of glutamatergic signaling in the nucleus accumbens of mice. Molecular and cellular neurosciences Asim, M., Hao, B., Waris, A., Liang, Y. M., Wang, X. G. 2022; 120: 103723

  Abstract

  Post-traumatic stress disorder (PTSD) is a devastating mental illness with high morbidity and major social and economic burden. Currently, there is no promising therapy available for the treatment of PTSD. Some clinical studies showed that ketamine could effectively alleviate PTSD symptoms. However, it is still unclear which brain region ketamine targets and how it attenuates the PTSD-like effects. In this study, we examined the effect of ketamine on fear generalization (a core symptom of PTSD) by using a mice model of fear generalization induced by fear conditioning procedure. Before retrieval, ketamine was locally infused into the nucleus accumbens (a brain region closely associated with PTSD). Fear generalization mice were subjected to behavioral testing and biochemical assessments, following ketamine infusion. The results showed that the foot shock strength-dependently induced fear generalization in mice with increased c-fos activity, and a lower level of GluR1(S845), GluR1(S831) protein, and a higher level of P-GluN2B protein in the nucleus accumbens (NAc). Local infusion of ketamine into NAc decreased the fear generalization together with an increased level of GluR1(S845), GluR1(S831) protein, and decreased level of P-GluN2B protein. Altogether, these results conclude that ketamine might affect the glutamatergic signaling in the NAc to attenuate the fear generalization in mice.

  View details for DOI 10.1016/j.mcn.2022.103723

  View details for PubMedID 35351607

• Ketamine for post-traumatic stress disorders and it's possible therapeutic mechanism. Neurochemistry international Asim, M., Wang, B., Hao, B., Wang, X. 2021; 146: 105044

  Abstract

  Posttraumatic stress disorder (PTSD) is a devastating medical illness, for which currently available pharmacotherapies have poor efficacy. Accumulating evidence from clinical and preclinical animal investigations supports that ketamine exhibits a rapid and persistent effect against PTSD, though the underlying molecular mechanism remains to be clarified. In this literature review, we recapitulate the achievements from early ketamine studies to the most up-to-date discoveries, with an effort to discuss an inclusive therapeutic role of ketamine for PTSD treatment and its possible therapeutic mechanism. Ketamine seems to have an inimitable mechanism of action entailing glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity.

  View details for DOI 10.1016/j.neuint.2021.105044

  View details for PubMedID 33862176

• Ketamine Alleviates Fear Generalization Through GluN2B-BDNF Signaling in Mice. Neuroscience bulletin Asim, M., Hao, B., Yang, Y. H., Fan, B. F., Xue, L., Shi, Y. W., Wang, X. G., Zhao, H. 2020; 36 (2): 153-164

  Abstract

  Fear memories are critical for survival. Nevertheless, over-generalization of these memories, depicted by a failure to distinguish threats from safe stimuli, is typical in stress-related disorders. Previous studies have supported a protective role of ketamine against stress-induced depressive behavior. However, the effect of ketamine on fear generalization remains unclear. In this study, we investigated the effects of ketamine on fear generalization in a fear-generalized mouse model. The mice were given a single sub-anesthetic dose of ketamine (30 mg/kg, i.p.) 1 h before, 1 week before, immediately after, or 22 h after fear conditioning. The behavioral measure of fear (indicated by freezing level) and synaptic protein expression in the basolateral amygdala (BLA) and inferior-limbic pre-frontal cortex (IL-PFC) of mice were examined. We found that only ketamine administered 22 h after fear conditioning significantly decreased the fear generalization, and the effect was dose-dependent and lasted for at least 2 weeks. The fear-generalized mice showed a lower level of brain-derived neurotrophic factor (BDNF) and a higher level of GluN2B protein in the BLA and IL-PFC, and this was reversed by a single administration of ketamine. Moreover, the GluN2B antagonist ifenprodil decreased the fear generalization when infused into the IL-PFC, but had no effect when infused into the BLA. Infusion of ANA-12 (an antagonist of the BDNF receptor TrkB) into the BLA or IL-PFC blocked the effect of ketamine on fear generalization. These findings support the conclusion that a single dose of ketamine administered 22 h after fear conditioning alleviates the fear memory generalization in mice and the GluN2B-related BDNF signaling pathway plays an important role in the alleviation of fear generalization.

  View details for DOI 10.1007/s12264-019-00422-4

  View details for PubMedID 31444653

  View details for PubMedCentralID PMC6977810

• The dilemma of epilepsy diagnosis in Pakistan. Diagnosis (Berlin, Germany) Waris, A., Asim, M., Ullah, A. 2024; 11 (3): 333-334

  View details for DOI 10.1515/dx-2024-0037

  View details for PubMedID 38485202

• Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action FRONTIERS IN PHARMACOLOGY Waris, A., Ullah, A., Asim, M., Ullah, R., Rajdoula, M., Bello, S., Alhumaydhi, F. A. 2024; 15: 1403232

  Abstract

  Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

  View details for DOI 10.3389/fphar.2024.1403232

  View details for Web of Science ID 001240414200001

  View details for PubMedID 38855752

  View details for PubMedCentralID PMC11160429

• Various pharmacological agents in the pipeline against intractable epilepsy ARCHIV DER PHARMAZIE Waris, A., Asim, M., Ullah, A., Alhumaydhi, F. A. 2024; 357 (9): e2400229

  Abstract

  Epilepsy is a noncommunicable chronic neurological disorder affecting people of all ages, with the highest prevalence in low and middle-income countries. Despite the pharmacological armamentarium, the plethora of drugs in the market, and other treatment options, 30%-35% of individuals still show resistance to the current medication, termed intractable epilepsy/drug resistance epilepsy, which contributes to 50% of the mortalities due to epilepsy. Therefore, the development of new drugs and agents is needed to manage this devastating epilepsy. We reviewed the pipeline of drugs in "ClinicalTrials. gov," which is the federal registry of clinical trials to identify drugs and other treatment options in various phases against intractable epilepsy. A total of 31 clinical trials were found regarding intractable epilepsy. Among them, 48.4% (15) are about pharmacological agents, of which 26.6% are in Phase 1, 60% are in Phase 2, and 13.3% are in Phase 3. The mechanism of action or targets of the majority of these agents are different and are more diversified than those of the approved drugs. In this article, we summarized various pharmacological agents in clinical trials, their backgrounds, targets, and mechanisms of action for the treatment of intractable epilepsy. Treatment options other than pharmacological ones, such as devices for brain stimulation, ketogenic diets, gene therapy, and others, are also summarized.

  View details for DOI 10.1002/ardp.202400229

  View details for Web of Science ID 001227210300001

  View details for PubMedID 38767508

• Recent advancement, immune responses, and mechanism of action of various vaccines against intracellular bacterial infections. Life sciences Ali, A., Waris, A., Khan, M. A., Asim, M., Khan, A. U., Khan, S., Zeb, J. 2023; 314: 121332

  Abstract

  Emerging and re-emerging bacterial infections are a serious threat to human and animal health. Extracellular bacteria are free-living, while facultative intracellular bacteria replicate inside eukaryotic host cells. Many serious human illnesses are now known to be caused by intracellular bacteria such as Salmonella enterica, Escherichia coli, Staphylococcus aureus, Rickettsia massiliae, Chlamydia species, Brucella abortus, Mycobacterium tuberculosis and Listeria monocytogenes, which result in substantial morbidity and mortality. Pathogens like Mycobacterium, Brucella, MRSA, Shigella, Listeria, and Salmonella can infiltrate and persist in mammalian host cells, particularly macrophages, where they proliferate and establish a repository, resulting in chronic and recurrent infections. The current treatment for these bacteria involves the application of narrow-spectrum antibiotics. FDA-approved vaccines against obligate intracellular bacterial infections are lacking. The development of vaccines against intracellular pathogenic bacteria are more difficult because host defense against these bacteria requires the activation of the cell-mediated pathway of the immune system, such as CD8+ T and CD4+ T. However, different types of vaccines, including live, attenuated, subunit, killed whole cell, nano-based and DNA vaccines are currently in clinical trials. Substantial development has been made in various vaccine strategies against intracellular pathogenic bacteria. This review focuses on the mechanism of intracellular bacterial infection, host immune response, and recent advancements in vaccine development strategies against various obligate intracellular bacterial infections.

  View details for DOI 10.1016/j.lfs.2022.121332

  View details for PubMedID 36584914

• Applications of Various Types of Nanomaterials for the Treatment of Neurological Disorders. Nanomaterials (Basel, Switzerland) Waris, A., Ali, A., Khan, A. U., Asim, M., Zamel, D., Fatima, K., Raziq, A., Khan, M. A., Akbar, N., Baset, A., Abourehab, M. A. 2022; 12 (13)

  Abstract

  Neurological disorders (NDs) are recognized as one of the major health concerns globally. According to the World Health Organization (WHO), neurological disorders are one of the main causes of mortality worldwide. Neurological disorders include Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Prion disease, Brain tumor, Spinal cord injury, and Stroke. These diseases are considered incurable diseases because no specific therapies are available to cross the blood-brain barrier (BBB) and reach the brain in a significant amount for the pharmacological effect in the brain. There is a need for the development of strategies that can improve the efficacy of drugs and circumvent BBB. One of the promising approaches is the use of different types of nano-scale materials. These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity. Different types and shapes of nanomaterials have been widely used for the treatment of neurological disorders, including quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These nanoparticles have unique characteristics, including sensitivity, selectivity, and the ability to cross the BBB when used in nano-sized particles, and are widely used for imaging studies and treatment of NDs. In this review, we briefly summarized the recent literature on the use of various nanomaterials and their mechanism of action for the treatment of various types of neurological disorders.

  View details for DOI 10.3390/nano12132140

  View details for PubMedID 35807977

  View details for PubMedCentralID PMC9268720