Case Record

UNDIFFERENTIATED SCHIZOPHRENIA: Mr. R was reported to be normal 4 years back, he was found to be preoccupied and not communicating well with his family members and preferred to stay alone. He was talking and laughing to self. When asked he said that he heard voices speaking to him and he were replying to it. Gradually his sleep decreased and he would sleep only for 3 to 4 hours at night. He did not attend classes. He was started washing his room many times. He was taking bath frequently. He was started worshiping god Anjanaya many times a day and also avoiding to speak with female family members. This continued for 2 months after which he started to be abusive and assaultive others for no reason. So he was taken to a psychiatrist, was admitted for 10 days and treated with ECT. After discharge he would discontinue medications on and off during which his symptoms would get exacerbated. He continued his studies but performance was poor. He also exhibited suicidal gestures on three occasions in the form of cutting his harms and carrying kerosene and matchbox inside the bathroom, saved by family members. Again the mother took him to psychiatrist and continued medication the symptoms were under the control. He completed his course but did not complete his studies. Then he got employment into Ford Company, his performance was average, he continued his job for 5 months with medication. After discontinue of treatment he became self-withdrawn, slowly he was neglecting self-care, attempted suicide, coworkers informed to his parents. Hence he was brought to IMH and admitted. No H/O sad mood, crying spells. No H/O tall claims, spending spree. No H/O thoughts being known to others or withdrawn. No H/O substance use. No H/O head injury, LOC, seizures. No H/O fever or any prolonged drug intake. SUBSTANCE INDUCED MOOD DISORDER: The patient was introduced to using betelnut along with his friends around 18 years of age. Later be continued to use tobacco in the form of Panparag, Hans, Shanthi betelnut 4-6 packets per day. Later after 3 years of tobacco intake, he started consuming alcohol for the first time along with his friends on some occasion, he consumed beer around 200ml. As he enjoyed the high produced by the drink, he continued to take alcohol at regular interval. After 1 year of beginning alcohol intake, he got married, after 6months of marriage life he started consuming alcohol in the form of brandy almost every night. He would become intoxicated, come home, abuse and assault his wife frequently. Due to frequent marrital dishormony his wife left and living with her grand parants for past 8 months. Now according to his be continued to drink alcohol, but the past two months he was engaged in some temple work, where he is supposedto have been introduced to cannabis.After consuming cannabis, his behavior became unmanageble. He frequently keep standing in the middle of the road and appear to make gesturesas if regulating the traffic. He would keep talking excessively and laugh for unprovoked reasons. His sleep patterns also worsened. All through out the night he would keep wandering in the street. And also he was started talking irrelevantly and would not be able to brought back home. He would also talk high about himself. He would claim himself to be God and capable of doing lot of things and able to grant wishes to all people. His selfcare also deteriorated, he started picking up quarrles and assaulted others. Nighbours made complaint against him. So, the family members brought him in the confused state to IMH. He was treated with Ing. Lorazepam 4 mg IM stat and referred to GGH for favour ofadmission and rule out other causes of delirium. He was treated at GGH for one week with Inj. Haloperidal 5 mg, Inj. Lorazepam 4 mg im, Inj.Thiamine and has been referred to IMH for further management. No h/o head injury/LOC/seizures. No h/o low mood/crying spells/suicidal attempts. No h/o hearing voices No h/o repititive washing/cheeking etc., DELUSIONAL DISORDER-MIXED: The patient was reported to be normal till one year eight months back. She claimed hat her co-tenant Mr. V called her for sexual relationship and she refused after that she started telling that he is setting people against her to harm her and also setup prostitutes as a co-tenants, to move her away from the place She also says that he tried to kill her with ambulance 108 and milk van by using his political influence. Patient gave complaint in nearby police station about Mr. Enquiry done. But the police Also turned against her by his political influence. So, she used to go to SP office, collector office daily and shout to arrest Mr. V. Mean while she vacated that house and shifted to Mr. S house who is friend of her brother. He is a widower, living alone. After 2 months of shifting to new house she started believing that the house owner was deeply loved with her whom she understands by his Gestures. And he did not admit his love for her has he did not want others to know. She was fought with the co-tenant once for silly reason. They were assaulted her with an aluminum mug and broken house hold article. And she assumed that Mr. V. only arranged them to fight with her. And also without any reason the patient was fought with the female Co-tenants whoever talking to Mr. S. She uses to tell everybody that the Mr. S. loves with her. The house owner warned them to vacate the house. But she did not vacate the house. The house owner slowly cut power supply, water supply to her portion. After 4 months she vacated the house to Next Street. Even after vacating, patient goes to Mr. S. house and starts quarrel with the new tenants that they should vacate and only because of them he is avoiding her. Every day she was going to her old house and tells everybody that the house owner loves with her. The husband told her not to go there, but she poured kerosene on him and try to kill him. So, the house owner filed a case against her, she was arrested and kept in observation at IMH. During observation she was continuously blaming the old co-tenant that all because him only it happen. Still the house owner his loves with her, she also loves him deeply. DEMENTIA IN ALZHEIMER’S DISEASE: The patient was reported to be normal till one year back. Then, her daughter noticed that the patient repeatedly searched for certain things in the house. She would forget simple things in the house like the way for going to toilet. At times she also found it difficult to return to her house after going for a walk. In course of time, she was not able to identify her close relatives. She was not able to remember whether she had taken her food or not. Her personal hygiene decreased gradually. She did not take bath and did not dress properly. She would pass urine inside the house itself at times. She slept for very little time and would wake up in the middle of the night and keep pacing inside the house.Slowly she was not able to identify her own family members. MENTAL RETARDATION-MILD: Patient was born out of non consanguineous marriage, full term normal delivery. Mother was 22 yrs and fathers age was 298 yrs. No history of any drug intake, fever or exanthematous eruptions in the ante natal period. No ante natal checkup was done. No history of radiation, injury, malnutrition, or vaginal bleeding. Delivery was conducted by local dhai; h/o prolonged 2nd stage of labor, the baby cried soon after birth and was breast fed after a short while. No h/o neonatal seizures or difficulty in feeding. No h/o of jaundice, breast fed up to 10 months, and there were no weaning difficulties

Development of novel small-size peptides as putative therapeutic drugs

This thesis focuses on the development of small peptide molecules with either antifungal properties or with the ability to control protein deposits that cause the characteristic brain damage in Alzheimer's disease (AD). Thus, our ultimate aim is to design putative therapeutic agents supported by computational techniques. Apropos of AD, this is a very complex disease where brain damage is associated with the degradation of the human mind and memory. Currently, researchers consent that a key role is played by a peptide called beta-amyloid. This peptide is not toxic by itself, however it becomes toxic to nerve-cells when several of its molecules clump together forming aggregates. This is the beginning of a slow but unstoppable brain deterioration, which ultimately leads to dementia. The currently available AD drugs delay, at best, the loss of memory, but do not stop the neural degradation. Its severity and the increasing number of AD patients, are the worldwide driving force to acquire more effective drugs. In our own research we focused on the development of new peptides that prevent or slow down the formation of the aggregated beta-amyloid. Computational techniques allowed us to explore the self-bound beta-amyloid molecules, as well as their interaction with new potential drugs. With this fascinating information we designed small peptides aimed at disrupting the aggregated beta-amyloid. Then, its anti-amyloid activity of was tested in vitro and in vivo. Both tests have produced not only positive but also striking and promising results indicating the potential therapeutic application of these new anti-amyloid peptides.

A metabolic perspective of late onset Alzheimer's disease

After decades of research, the molecular neuropathology of Alzheimer's disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid β (Aβ) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aβ oligomers as mere aggravators, with an arguable role in the origin of the disease. In this line of research, the relative contribution of soluble Aβ oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aβ production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment. The present review summarizes the current understanding on the neuropathological role of Aβ associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD). Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer’s disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening

Development of small-molecule libraries for neurodegenerative protein misfolding diseases

Protein misfolding diseases (PMDs) are chronic and progressively degenerative disorders, characterized by the accumulation of insoluble aggregates of misfolded proteins. Particularly, amyloid-\u3b2 and tau protein in Alzheimer\u2019s disease, prion protein in prion diseases, and \u3b1-synuclein in Parkinson disease are prototypical misfolded proteins that aggregate and accumulate in the brain, being responsible for the respective neurodegenerative disease. In the last decades, neurodegenerative PMDs have drawn public and scientific attention due to an increasing number of cases, becoming a critical issue in terms of healthcare and social costs. Moreover, while the list of neurodegenerative PMDs is long and growing, the pipeline of disease-modifying drugs is dry. In light of this clear unmet medical need, the present PhD thesis has been devoted to the development of three small-molecule libraries for neurodegenerative PMDs, through different and innovative strategies. First, we applied the multi-target directed ligand approach and we developed the first class of multi-target compounds able to hit the tau cascade at two different hubs. The synthesized 2,4-thiazolidinedione derivatives were able to concomitantly inhibit the phosphorylating tau kinase GSK-3\u3b2, as well as the tau aggregation process. Thus, these multi-target compounds could be promising tools for the validation of a completely new tau-centric approach as a disease-modifying strategy to treat Alzheimer\u2019s disease. Secondly, we applied the theranostic approach and we designed and synthesized a library of fluorescent bivalent derivatives. These bivalent compounds could be able, in principle, to stain A\u3b2 and tau protein aggregates and to inhibit the protein aggregation process. If we will be able to further demonstrate their theranostic profile in vitro and in vivo, these compounds could serve as innovative tools to potentially diagnose, deliver therapy, and monitor response to therapy in PMDs. Finally, we designed a focused library of compounds with the aim of optimizing the drug-like properties of a previously identified antiprion compound. Namely, we inserted on a position amenable to derivatization solubilizing groups, specifically tailored for CNS drug optimization. If our design strategy will be successful, we will have improved the pharmacokinetic properties of a promising antiprion compound, making possible its progression to further in vivo studies

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia

CORAL: The dispersion of SWNTs in different organic solvents

Single-walled carbon nanotubes (SWNTs) are group of new substances with specific cylindrical architecture of their molecules. The dispersion of SWNTs in different organic solvents is parameter that can be valuable information for development of nanomaterials. The CORAL software is a tool to build up model for different endpoints using the Monte Carlo technique. In this work, the ability of the CORAL software to be a tool to predict dispersion of SWCTs in different organic solvents demonstrated

Trends in the Molecular Pathogenesis and Clinical Therapeutics of Common Neurodegenerative Disorders

The term neurodegenerative disorders, encompasses a variety of underlying conditions, sporadic and/or familial and are characterized by the persistent loss of neuronal subtypes. These disorders can disrupt molecular pathways, synapses, neuronal subpopulations and local circuits in specific brain regions, as well as higher-order neural networks. Abnormal network activities may result in a vicious cycle, further impairing the integrity and functions of neurons and synapses, for example, through aberrant excitation or inhibition. The most common neurodegenerative disorders are Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis and Huntington’s disease. The molecular features of these disorders have been extensively researched and various unique neurotherapeutic interventions have been developed. However, there is an enormous coercion to integrate the existing knowledge in order to intensify the reliability with which neurodegenerative disorders can be diagnosed and treated. The objective of this review article is therefore to assimilate these disorders’ in terms of their neuropathology, neurogenetics, etiology, trends in pharmacological treatment, clinical management, and the use of innovative neurotherapeutic interventions