Pregnant in the United States in the COVID-19 pandemic: A collision of crises we cannot ignore.

NO abstract intended, Introduction is listed here The COVID-19 pandemic and call for social justice is occurring when the United States, unlike its peer countries, has already experienced a steady 20-year rise in maternal morbidity and mortality with pregnant women today facing a 50 percent higher risk of mortality than their mothers. 1 Most vulnerable are women of color, black and American Indian/Alaska Native women, who have experienced longstanding disparities in access to and quality of healthcare and may begin pregnancy with hypertension, diabetes, and obesity, complications known to be more common in women enduring segregation. 2-4 Initially, the race-related health disparities and resultant disproportionately higher rates of COVID-19 cases and mortality in indigenous communities and black, latinx, or other communities of color were mistakenly considered innate racial differences. More recently, these higher rates have been attributed to underlying social, structural, and environmental determinants of health including resource inequities, inadequate housing, and occupational and environmental hazards that result in greater exposure to and less protection from COVID-19. 5,6 Augmented by the added physiologic stress of pregnancy, these comorbidities and disparities compound the risk of pregnancy-associated cardiomyopathy, thromboembolism, and hemorrhage, often resulting in lasting physical and mental health consequences.

The safety of asthma medications during pregnancy and lactation: Clinical management and research priorities.

Asthma is one of the most common underlying diseases in women of reproductive age that can lead to potentially serious medical problems during pregnancy and lactation. A group of key stakeholders across multiple relevant disciplines was invited to take part in an effort to prioritize, strategize, and mobilize action steps to fill important gaps in knowledge regarding asthma medication safety in pregnancy and lactation. The stakeholders identified substantial gaps in the literature on the safety of asthma medications used during pregnancy and lactation and prioritized strategies to fill those gaps. Short-term action steps included linking data from existing complementary study designs (US and international claims data, single drug pregnancy registries, case-control studies, and coordinated systematic data systems). Long-term action steps included creating an asthma disease registry, incorporating the disease registry into electronic health record systems, and coordinating care across disciplines. The stakeholders also prioritized establishing new infrastructures/collaborations to perform research in pregnant and lactating women and to include patient perspectives throughout the process. To address the evidence gaps, and aid in populating product labels with data that inform clinical decision making, the consortium developed a plan to systematically obtain necessary data in the most efficient and timely manner.

Relations between catechol-O-methyltransferase Val158Met genotype and inhibitory control development in childhood.

The Val158Met rs4680 single-nucleotide polymorphism (SNP) at the catechol-O-methyltransferase (COMT) gene, primarily involved in dopamine breakdown within prefrontal cortex, has shown relations with inhibitory control (IC) in both adults and children. However, little is known about how COMT genotype relates to developmental trajectories of IC throughout childhood. Here, our study explored the effects of the COMT genotype (Val/Val, Val/Met, and Met/Met) on IC trajectories between the ages of 5 and 10 years. Children (n = 222) completed a Go/Nogo task at ages 5, 7, and 10; IC was characterized using signal detection theory to examine IC performance (d') and response strategy (RS) (criterion). COMT genotype was not related to initial levels of IC performance and RS at age 5 or change in RS from ages 5 to 10. In contrast, COMT genotype was related to change in IC performance between 5 and 10 years. While Val/Val children did not differ from Val/Met children in development of IC performance, children with the Met/Met genotype exhibited more rapid development of IC performance when compared with Val/Met peers. These results suggest that COMT genotype modulates the development of IC performance in middle childhood.

GABBR1 and SLC6A1, Two Genes Involved in Modulation of GABA Synaptic Transmission, Influence Risk for Alcoholism: Results from Three Ethnically Diverse Populations.

BACKGROUND: Animal and human studies indicate that GABBR1, encoding the GABAB1 receptor subunit, and SLC6A1, encoding the neuronal gamma-aminobutyric acid (GABA) transporter GAT1, play a role in addiction by modulating synaptic GABA. Therefore, variants in these genes might predict risk/resilience for alcoholism. METHODS: This study included 3 populations that differed by ethnicity and alcoholism phenotype: African American (AA) men: 401 treatment-seeking inpatients with single/comorbid diagnoses of alcohol and drug dependence, 193 controls; Finnish Caucasian men: 159 incarcerated alcoholics, half with comorbid antisocial personality disorder, 181 controls; and a community sample of Plains Indian (PI) men and women: 239 alcoholics, 178 controls. Seven GABBR1 tag single nucleotide polymorphisms were genotyped in the AA and Finnish samples; rs29220 was genotyped in the PI for replication. Also, a uniquely African, functional SLC6A1 insertion promoter polymorphism (IND) was genotyped in the AAs. RESULTS: We found a significant and congruent association between GABBR1 rs29220 and alcoholism in all 3 populations. The major genotype (heterozygotes in AAs, Finns) and the major allele in PIs were significantly more common in alcoholics. Moreover, SLC6A1 IND was more abundant in controls, that is, the major genotype predicted alcoholism. An analysis of combined GABBR1 rs29220 and SLC6A1 IND genotypes showed that rs29220 heterozygotes, irrespective of their IND status, had an increased risk for alcoholism, whereas carriers of the IND allele and either rs29220 homozygote were more resilient. CONCLUSIONS: Our results show that with both GABBR1 and SLC6A1, the minor genotypes/alleles were protective against risk for alcoholism. Finally, GABBR1 rs29220 might predict treatment response/adverse effects for baclofen, a GABAB receptor agonist.

Evidence of MAOA genotype involvement in spatial ability in males.

Although the monoamine oxidase-A (MAOA) gene has been linked to spatial learning and memory in animal models, convincing evidence in humans is lacking. Performance on an ecologically-valid, virtual computer-based equivalent of the Morris Water Maze task was compared between 28 healthy males with the low MAOA transcriptional activity and 41 healthy age- and IQ-matched males with the high MAOA transcriptional activity. The results revealed consistently better performance (reduced heading error, shorter path length, and reduced failed trials) for the high MAOA activity individuals relative to the low activity individuals. By comparison, groups did not differ on pre-task variables or strategic measures such as first-move latency. The results provide novel evidence of MAOA gene involvement in human spatial navigation using a virtual analogue of the Morris Water Maze task.

DRD4 and striatal modulation of the link between childhood behavioral inhibition and adolescent anxiety.

Behavioral inhibition (BI), a temperament characterized by vigilance to novelty, sensitivity to approach-withdrawal cues and social reticence in childhood, is associated with risk for anxiety in adolescence. Independent studies link reward hyper-responsivity to BI, adolescent anxiety and dopamine gene variants. This exploratory study extends these observations by examining the impact of DRD4 genotype and reward hyper-responsivity on the BI-anxiety link. Adolescents (N = 78) completed a monetary incentive delay task in the fMRI environment. Participants were characterized based on a continuous score of BI and the 7-repeat allele (7R+) of the DRD4 functional polymorphism. Parent-report and self-report measures of anxiety were also collected. Across the entire sample, striatal activation increased systematically with increases in the magnitude of anticipated monetary gains and losses. DRD4 status moderated the relation between BI and activation in the caudate nucleus. Childhood BI was associated with parent report of adolescent anxiety among 7R+ participants with elevated levels of striatal response to incentive cues. DRD4 genotype influenced the relations among neural response to incentives, early childhood BI and anxiety. The findings help refine our understanding of the role reward-related brain systems play in the emergence of anxiety in temperamentally at-risk individuals, building a foundation for future larger scale studies.

Loss aversion and 5HTT gene variants in adolescent anxiety.

Loss aversion, a well-documented behavioral phenomenon, characterizes decisions under risk in adult populations. As such, loss aversion may provide a reliable measure of risky behavior. Surprisingly, little is known about loss aversion in adolescents, a group who manifests risk-taking behavior, or in anxiety disorders, which are associated with risk-avoidance. Finally, loss aversion is expected to be modulated by genotype, particularly the serotonin transporter (SERT) gene variant, based on its role in anxiety and impulsivity. This genetic modulation may also differ between anxious and healthy adolescents, given their distinct propensities for risk taking. The present work examines the modulation of loss aversion, an index of risk-taking, and reaction-time to decision, an index of impulsivity, by the serotonin-transporter-gene-linked polymorphisms (5HTTLPR) in healthy and clinically anxious adolescents. Findings show that loss aversion (1) does manifest in adolescents, (2) does not differ between healthy and clinically anxious participants, and (3), when stratified by SERT genotype, identifies a subset of anxious adolescents who are high SERT-expressers, and show excessively low loss-aversion and high impulsivity. This last finding may serve as preliminary evidence for 5HTTLPR as a risk factor for the development of comorbid disorders associated with risk-taking and impulsivity in clinically anxious adolescents.

Independent effects of 5' and 3' functional variants in the serotonin transporter gene on suicidal behavior in the context of childhood trauma.

The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT). DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers. There were independent G × E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034-rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant. Our findings suggest that the 5' and 3'SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals.

Attention to threats and combat-related posttraumatic stress symptoms: prospective associations and moderation by the serotonin transporter gene.

IMPORTANCE: Combat places soldiers at risk for posttraumatic stress disorder (PTSD). The excessive rates of PTSD and other adjustment disorders in soldiers returning home make it imperative to identify risk and resilience factors that could be targeted by novel therapeutic treatments. OBJECTIVE: To investigate the interplay among attention to threat, combat exposure, and other risk factors for PTSD symptoms in soldiers deployed to combat. DESIGN AND SETTING: Longitudinal prospective study of Israeli Defense Force infantry soldiers carried out in 2008 through 2010. Repeated measurements during a 1-year period included baseline and predeployment data collected in training camps and deployment data collected in the combat theater. PARTICIPANTS: Infantry soldiers (1085 men; mean age, 18.8 years). MAIN OUTCOME MEASURES: Postcombat PTSD symptoms. RESULTS Soldiers developed threat vigilance during combat deployment, particularly when they were exposed to high-intensity combat, as indicated by faster response times to targets appearing at the location of threat relative to neutral stimuli (P < .001). Threat-related attention bias also interacted with combat exposure to predict risk for PTSD (P < .05). Bias toward threat at recruitment (P < .001) and bias away from threat just before deployment (P < .05) predicted postcombat PTSD symptoms. Moreover, these threat-related attention associations with PTSD were moderated by genetic and environmental factors, including serotonin transporter (5-HTTLPR) genotype. CONCLUSIONS AND RELEVANCE: Combat exposure interacts with threat-related attention to place soldiers at risk for PTSD, and interactions with other risk factors account for considerable variance in PTSD vulnerability. Understanding these associations informs research on novel attention bias modification techniques and prevention of PTSD.

Gray matter volume in adolescent anxiety: an impact of the brain-derived neurotrophic factor Val(66)Met polymorphism?

OBJECTIVE: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val(66)Met polymorphism may modulate such brain morphometry profiles. METHOD: Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 [corrected] Met allele carriers, 36 [corrected] Val/Val homozygotes). RESULTS: Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. CONCLUSIONS: These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC.

The MAOA gene predicts happiness in women.

Psychologists, quality of life and well-being researchers have grown increasingly interested in understanding the factors that are associated with human happiness. Although twin studies estimate that genetic factors account for 35-50% of the variance in human happiness, knowledge of specific genes is limited. However, recent advances in molecular genetics can now provide a window into neurobiological markers of human happiness. This investigation examines association between happiness and monoamine oxidase A (MAOA) genotype. Data were drawn from a longitudinal study of a population-based cohort, followed for three decades. In women, low expression of MAOA (MAOA-L) was related significantly to greater happiness (0.261 SD increase with one L-allele, 0.522 SD with two L-alleles, P=0.002) after adjusting for the potential effects of age, education, household income, marital status, employment status, mental disorder, physical health, relationship quality, religiosity, abuse history, recent negative life events and self-esteem use in linear regression models. In contrast, no such association was found in men. This new finding may help explain the gender difference on happiness and provide a link between MAOA and human happiness.

The influence of oxytocin administration on responses to infant faces and potential moderation by OXTR genotype.

RATIONALE: Oxytocin is a neuropeptide that is associated with increases in social affiliative behaviors, particularly toward infants. However, no previous study has investigated healthy adults' responses to infant faces following oxytocin administration. In addition, given that preliminary evidence suggests that a single-nucleotide polymorphism of the oxytocin receptor (OXTR) gene, rs53576, may influence behaviors associated with parental sensitivity, we assessed whether such responses vary according to OXTR rs53576 genotype. OBJECTIVES: The present study assessed the effects of intranasally administered oxytocin and OXTR genotype on human adults' preferences for infant faces. METHODS: A double-blind, between-groups design was used, with 57 genotyped volunteers randomly assigned to receive intranasally administered oxytocin or placebo. Fifty minutes following the administration of oxytocin or placebo, participants viewed infants' and adults' faces showing neutral expressions and assessed how appealing they found each face. RESULTS: Infants' faces were more strongly preferred following oxytocin inhalation relative to placebo. When participants were separated according to genotype, this effect was only observed for participants homozygous for the rs53576G allele. Parallel effects were not seen for adults' faces. CONCLUSIONS: The present results are consistent with the hypothesis that acute oxytocin administration increases sensitivity to reward-relevant features of infants and/or reduces sensitivity to their aversive properties. The results are also consistent with suggestions of more efficient oxytocinergic function in rs53576G homozygotes.

Serotonin transporter genotype (5-HTTLPR) predicts utilitarian moral judgments.

BACKGROUND: The psychological and neurobiological processes underlying moral judgment have been the focus of extensive recent research. Here we show that serotonin transporter (5-HTTLPR) genotype predicts responses to moral dilemmas featuring foreseen harm to an innocent. METHODOLOGY/PRINCIPAL FINDINGS: Participants in this study judged the acceptability of actions that would unintentionally or intentionally harm an innocent victim in order to save others' lives. An analysis of variance revealed a genotype × scenario interaction, F(2, 63) = 4.52, p = .02. Results showed that, relative to long allele homozygotes (LL), carriers of the short (S) allele showed particular reluctance to endorse utilitarian actions resulting in foreseen harm to an innocent individual. LL genotype participants rated perpetrating unintentional harm as more acceptable (M = 4.98, SEM = 0.20) than did SL genotype participants (M = 4.65, SEM = 0.20) or SS genotype participants (M = 4.29, SEM = 0.30). No group differences in moral judgments were observed in response to scenarios featuring intentional harm. CONCLUSIONS/SIGNIFICANCE: The results indicate that inherited variants in a genetic polymorphism that influences serotonin neurotransmission influence utilitarian moral judgments as well. This finding is interpreted in light of evidence that the S allele is associated with elevated emotional responsiveness.

Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide.

Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and is a known risk factor for suicidal behavior. In this study we sought to determine whether the impact of childhood trauma on suicide risk might be modified by FKBP5, an HPA-axis regulating gene. Sixteen FKBP5 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped in a sample of African Americans: 398 treatment-seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 nonsubstance-dependent individuals (40% men; 21 suicide attempters). In all, 474 participants (112 suicide attempters) also completed the Childhood Trauma Questionnaire (CTQ). Primary haplotype analyses were conducted with the four SNPs implicated in earlier studies: rs3800373, rs9296158, rs1360780, and rs9470080. We found that childhood trauma was associated with suicide attempt (P<0.0001). Although there was no main effect of the two major yin yang haplotypes in the four SNP haplotype blocks, there was a haplotype influence on suicide risk (p=0.006) only in individuals exposed to high levels of childhood trauma. In this group, 51% with two copies of the risk haplotype, 36% with one copy, and 20% with no copies had attempted suicide. The total logistic regression model accounted for 13% of the variance in attempted suicide. Analyses of the 16 SNPs showed significant main effects on suicide attempt of rs3777747, rs4713902, and rs9470080 and interactive effects of rs3800373, rs9296158, and rs1360780 with CTQ score on suicide attempt. These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide.

Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces.

Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N=117) were classified for presumed SLC6A4 expression based on 5-HTTLPR-low (SS, SL(G), or L(G)L(G)), intermediate (SL(A) or L(A)L(G)), or high (L(A)L(A)). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low>intermediate>high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation.

Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population.

BACKGROUND: Genetic polymorphisms that influence serotonin (5-hydroxytryptamine, 5HT) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the 5HT transporter (5HTTLPR), and/or a substitution polymorphism in the promoter region for the 5HT2A receptor, would be associated with PTSD in a trauma exposed population of adult African-Americans. METHODS: Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM-IV (SCID). 5HTTLPR and 5HT2A-1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele "dose", were analyzed. RESULTS: Fifty-five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The 5HT2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with 5HTTLPR. CONCLUSIONS: Our findings suggest a relationship between genetic variation in the 5HT2A promoter region and PTSD.

ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain.

The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

Effect of chronic treatment with ladostigil (TV-3326) on anxiogenic and depressive-like behaviour and on activity of the hypothalamic-pituitary-adrenal axis in male and female prenatally stressed rats.

OBJECTIVE: The aim of the study is to investigate the effect of ladostigil, a cholinesterase and brain-selective monoamine oxidase (MAO) inhibitor, on anxiogenic and depressive-like behaviour and the response of the hypothalamic-pituitary-adrenal axis to stress in prenatally stressed (PS) male and female rats. METHODS: Ladostigil (17 mg/kg/day) was administered daily for 6 weeks to control and PS rats aged 6 weeks. Behaviour was assessed in the elevated plus maze (EPM) and forced swim tests (FST). Plasma corticosterone (COR) was measured before, 30 and 90 min after exposure to stress. RESULTS: Ladostigil inhibited brain MAO-A and B by more than 60%, significantly reduced hyperanxiety of male and female PS rats in the EPM and depressive-like behaviour in the FST without affecting that of controls and restored the delayed return to baseline of plasma COR in PS rats after exposure to stress to that of control rats. CONCLUSIONS: A novel brain-selective MAO inhibitor, ladostigil can selectively reverse the behavioural and neurochemical effects induced by prenatal stress without affecting the behaviour of controls.

A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease.

Degeneration of cholinergic cortical neurons is one of the main reasons for the cognitive deficit in dementia of the Alzheimer type (AD) and in dementia with Lewy bodies (DLB). Many subjects with AD and DLB have extrapyramidal dysfunction and depression resulting from degeneration of dopaminergic, noradrenergic and serotoninergic neurons. We prepared a novel drug, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), with both cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity, as potential treatment of AD and DLB. TV-3326 inhibits brain acetyl and butyrylcholinesterase (BuChE) in rats after oral doses of 10-100 mg/kg. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain by more than 70% but has almost no effect on these enzymes in the small intestine in rats and rabbits. The brain selectivity results in minimal potentiation of the pressor response to oral tyramine. TV-3326 acts like other antidepressants in the forced swim test in rats, indicating a potential for antidepressant activity. Chronic treatment of mice with TV-3326 (26 mg/kg) prevents the destruction of nigrostriatal neurons by the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In addition to ChE and MAO inhibition, the propargylamine moiety of TV-3326 confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells that results from prevention of the fall in mitochondrial membrane potential and antiapoptotic activity. These unique multiple actions of TV-3326 make it a potentially useful drug for the treatment of dementia with Parkinsonian-like symptoms and depression.