Clinical Trials Of Neuroprotection Research Articles

Trends in glaucoma: Update on clinical trials and new targets to treat glaucoma

AbstractClinical trials with glaucoma have increased significantly over the last 30 years. The three main areas of clinical trials are in diagnostic tools, medical treatments, and new surgical strategies. While medical treatments have been the most common clinical trials, the number of clinical trials in surgery is now leading. In medical care, most new goals are new IOP‐lowering strategies, whereas clinical trials of neuroprotection and vascular modalities are still sparse. In addition to traditional medicine, dietary supplements and growth factors are also assessed for a potential anti‐glaucomatous effect. Within medical targets, the success rates for Phases II and III are below the reported success rate for all diseases and ophthalmology in general. The reasons for the low success rates can be explained, among other things, by the need for a stricter phenotyping of patients. Here, an overview of trends in clinical trials will be given and a future perspective will be discussed.

Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade.

Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.

Core temperature after birth in babies with neonatal encephalopathy in a sub-Saharan African hospital setting.

Key points Therapeutic hypothermia (HT) to 33.0–34.0°C for 72 h provides optimal therapy for infants with neonatal encephalopathy (NE) in high‐resource settings. HT is not universally implemented in low‐ and middle‐income countries as a result of both limited resources and evidence.Facilitated passive cooling, comprising infants being allowed to passively lower their body temperature in the days after birth, is an emerging practice in some West African neonatal units.In this observational study, we demonstrate that infants undergoing facilitated passive cooling in a neonatal unit in Accra, Ghana, achieve temperatures within the HT target range ∼20% of the 72 h. Depth of HT fluctuates and can be excessive, as well as not maintained, especially after 24 h.Sustained and deeper passive cooling was evident for severe NE and for those that died.It is important to prevent excessive cooling, to understand that severe NE babies cool more and to be aware of facilitated passive cooling with respect to the design of clinical trials in low‐ and mid‐resource settings. Neonatal encephalopathy (NE) is a significant worldwide problem with the greatest burden in sub‐Saharan Africa. Therapeutic hypothermia (HT), comprising the standard of care for infants with moderate‐to‐severe NE in settings with sophisticated intensive care, is not available to infants in many sub‐Saharan African countries, including Ghana. We prospectively assessed the temperature response in relation to outcome in the 80 h after birth in a cohort of babies with NE undergoing ‘facilitated passive cooling’ at Korle Bu Teaching Hospital, Accra, Ghana. We hypothesized that NE infants demonstrate passive cooling. Thirteen infants (69% male) ≥36 weeks with moderate‐to‐severe NE were enrolled. Ambient mean ± SD temperature was 28.3 ± 0.7°C. Infant core temperature was 34.2 ± 1.2°C over the first 24 h and 35.0 ± 1.0°C over 80 h. Nadir mean temperature occurred at 15 h. Temperatures were within target range for HT with respect to 18 ± 14% of measurements within the first 72 h. Axillary temperature was 0.5 ± 0.2°C below core. Three infants died before discharge. Core temperature over 80 h for surviving infants was 35.3 ± 0.9°C and 33.96 ± 0.7°C for those that died (P = 0.043). Temperature profile negatively correlated with Thompson NE score on day 4 (r 2 = 0.66): infants with a Thompson score of 0–6 had higher temperatures than those with a score of 7–15 (P = 0.021) and a score of 16+/deceased (P = 0.007). More severe NE was associated with lower core temperatures. Passive cooling is a physiological response after hypoxia–ischaemia; however, the potential neuroprotective effect of facilitated passive cooling is unknown. An awareness of facilitated passive cooling in babies with NE is important for the design of clinical trials of neuroprotection in low and mid resource settings.

Cardiac Arrest Outcomes in Children With Preexisting Neurobehavioral Impairment.

To describe survival and 3-month and 12-month neurobehavioral outcomes in children with preexisting neurobehavioral impairment enrolled in one of two parallel randomized clinical trials of targeted temperature management. Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials data. Forty-one PICUs in the United States, Canada, and United Kingdom. Eighty-four participants (59 in-hospital cardiac arrest and 25 out-of-hospital cardiac arrest), 49 males, 35 females, mean age 4.6 years (SD, 5.36 yr), with precardiac arrest neurobehavioral impairment (Vineland Adaptive Behavior Scales, Second Edition composite score < 70). All required chest compressions for greater than or equal to 2 minutes, were comatose and required mechanical ventilation after return of circulation. Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting precardiac arrest status), and at 3 and 12 months postcardiac arrest, followed by on-site cognitive evaluation. Vineland Adaptive Behavior Scales, Second Edition norms are 100 (mean) ± 15 (SD); higher scores indicate better function. Analyses evaluated survival, changes in Vineland Adaptive Behavior Scales, Second Edition, and cognitive functioning. Twenty-eight of 84 (33%) survived to 12 months (in-hospital cardiac arrest, 19/59 (32%); out-of-hospital cardiac arrest, 9/25 [36%]). In-hospital cardiac arrest (but not out-of-hospital cardiac arrest) survival rate was significantly lower compared with the Therapeutic Hypothermia after Pediatric Cardiac Arrest group without precardiac arrest neurobehavioral impairment. Twenty-five survived with decrease in Vineland Adaptive Behavior Scales, Second Edition less than or equal to 15 (in-hospital cardiac arrest, 18/59 (31%); out-of-hospital cardiac arrest, 7/25 [28%]). At 3-months postcardiac arrest, mean Vineland Adaptive Behavior Scales, Second Edition scores declined significantly (-5; SD, 14; p < 0.05). At 12 months, Vineland Adaptive Behavior Scales, Second Edition declined after out-of-hospital cardiac arrest (-10; SD, 12; p < 0.05), but not in-hospital cardiac arrest (0; SD, 15); 43% (12/28) had unchanged or improved scores. This study demonstrates the feasibility, utility, and challenge of including this population in clinical neuroprotection trials. In children with preexisting neurobehavioral impairment, one-third survived to 12 months and their neurobehavioral outcomes varied broadly.

Cold blood perfusion for selective hypothermia in acute ischemic stroke.

Hypothermia is the most reliably effective neuroprotectant, and yet systemic complications limit application. A large body of animal data suggests that hypothermia is effective for focal cerebral ischemia, namely acute ischemic stroke. In order to apply hypothermia effectively, a selective approach is required to maximize the effect on the brain while minimizing systemic side effects. Due to poor transferability of promising findings in rodent models to human clinical trials for neuroprotection, the focus of this review is large animal gyrencephalic models. Unlike rodent data which favor mild hypothermia, the majority of large animal studies on selective hypothermia support moderate-to-deep hypothermia (<30°C). Cold blood perfusion produces the rapid rate of temperature reduction and depth of hypothermia required to produce meaningful neuroprotection. Further studies of selective hypothermia in acute ischemic stroke require attention to duration and rate of cooling to optimize the neuroprotection offered by this technique.

Neuroimaging of Rapid Eye Movement Sleep Behavior Disorder.

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a parasomnia characterized by the loss of muscle atonia and the presence of undesirable motor manifestations during rapid eye movement sleep. Research findings have shown that iRBD is a prodromal stage of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. A wide array of neuroimaging techniques have improved our understanding of the prodromal stage of these diseases in patients with iRBD, and identified potential biomarkers. In this chapter, we summarize current knowledge about functional and structural central and peripheral neuroimaging in iRBD, including cross-sectional and longitudinal studies using positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging, and transcranial sonography. Current neuroimaging research has revealed several brain alterations in iRBD similar to those reported in synucleinopathies, thereby improving our understanding of the pathophysiology underlying the clinical presentation and progression of their prodromal stages. Moreover, some abnormalities detected by neuroimaging show promise as potential biomarkers to predict which individuals with iRBD may be at risk of conversion and therefore candidates for inclusion in future clinical trials of neuroprotection.

Regeneration after stroke: Stem cell transplantation and trophic factors.

Stroke is a leading cause of death and disability worldwide. However, there is only one Food and Drug Administration-approved drug for the treatment of ischemic stroke, i.e., tissue plasminogen activator, and its therapeutic window is limited to within 4.5 h after stroke. Since clinical trials for neuroprotection have failed to demonstrate efficacy, multipotent and pluripotent stem cell transplantations are viable candidates for stroke treatment by providing trophic factor support and/or cell replacement following injury. The goal of this review is to highlight the promise of stem cell transplantation as vehicles for trophic factor delivery. The beneficial effects of different stem cell types as transplants as well as ways to upregulate trophic factors in stem cells are described in this review. Stem cell transplantation has consistently shown beneficial effects in the ischemic stroke model, in part due to the beneficial factors that stem cells release around the stroke injury area, resulting in smaller infarct volumes and regeneration and functional recovery. Upregulation of beneficial factors in stem cells and neural progenitors before transplantation has been shown to be even more effective in treating the stroke injury than stem cells without upregulated factors. However, for both stem cells and genetic engineering, there remain many unanswered questions and potential for improvement. These include modifiable parameters such as the different stem cell types and different factors, as well as the various readouts for investigation, such as various in vivo effects, such as immune system modulation and enhancement of endogenous neurogenesis and angiogenesis.

Diagnosis and Treatment of Corticobasal Degeneration

Corticobasal degeneration is a pathologic entity. Presenting clinical phenotypes include corticobasal syndrome (CBS), frontal behavioral spatial syndrome, aphasia, progressive supranuclear palsy-like syndrome (PSPS), and a predominantly cognitive phenotype often mistaken for Alzheimer's disease (AD). Treatment of CBD is symptomatic, particularly given recently negative neuroprotective studies. Given the relentless progression in CBD, all interested patients should be offered the opportunity to enroll in clinical neuroprotective trials as they arise. For symptomatic therapy, treatment options are necessarily based on evidence from other disorders given the lack of studies in CBD. In patients with CBS and PSPS, parkinsonism is treated with levodopa/carbidopa. This generally has modest and transient benefits at best and often results in no improvement. Botulinum toxin injections are the treatment of choice for limb dystonia. Clonazepam and levetiracetam are commonly used for myoclonus. Physical therapy is an important part of motor treatment, particularly for fall prevention strategies and assist device assessment. Whether medications such as cholinesterase inhibitors or memantine have any role in CBD is unclear given the various responses described in related phenotypes and diseases. Treating the behavioral symptoms associated with CBD is critical in an attempt to treat symptoms for which we have good pharmacologic interventions and to hopefully improve quality of life. General supportive care is important, including assessing for sores related to dystonia or immobility, monitoring dysphagia, and identifying needs for support services. Finally, as with other relentlessly progressive neurodegenerative diseases, it is critical to provide family and caregiver support and to assess for when palliative care services will serve the patient best.

Neuroprotective strategies for traumatic brain injury: improving clinical translation.

Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.

Gabapentin is neuroprotective through glutamate receptor-independent mechanisms in staurosporine-induced apoptosis of cultured rat cerebellar neurons

Abstract The anticonvulsants that are currently available modulate the activity of neuronal receptors and ion channels, which are equally involved in apoptotic pathways. We investigated the hypothesis that gabapentin (GP), an anticonvulsant without effect on glutamate receptors acting as GABA analog, has neuroprotective properties. For comparison, we chose topiramate (TPM), which has been reported to be neuroprotective via AMPA receptors blockade. For this purpose, we used rat cerebellar granule neuron (CGN) cultures and we triggered apoptosis independent of glutamate receptors with staurosporine, a broad-spectrum protein kinase inhibitor. GP at therapeutic range concentration significantly increased cell viability in CGN cultures maintained in physiological KCl concentration and reversed apoptosis induced by staurosporine. Blockade of NMDA or AMPA receptors by MK801 or NBQX, respectively, did not alter GP neuroprotection, which was reversed instead by GABA. In contrast, protective effect of TPM on STS-treated CGN cultures was annihilated by NBQX, and not altered by MK801 or GABA. Treatments with neuroprotective concentrations of GP or TPM did not modify the expression of neuronal cell adhesion molecule or synaptophysin or the morphological aspect of neuronal endings. In summary, we report that GP is neuroprotective through glutamate-receptor independent mechanisms and without alteration of neuronal plasticity markers, which makes it a possible candidate for clinical neuroprotection trials.

Novel Approaches to Neuroprotection Trials in Acute Ischemic Stroke

Cerebral neuroprotection for acute ischemic stroke (AIS) is defined as a therapy aimed at enhancing the brain’s resilience to ischemia to improve the clinical outcome of affected individuals. Although traditionally aimed at the salvage of neurons, this term may be equally applicable to all the cellular constituents of the brain, including cells of cerebral blood vessels, neurons, and glia. Pharmacological neuroprotection (hereafter referred to as neuroprotection) would be achieved by drugs targeting one or more critical components of the ischemic cascade that lead to ischemic damage. The feasibility of neuroprotection has a strong basis in animal experiments, but research for several decades has failed to translate neuroprotective treatments from animals to humans.1–3 The disappointing results of all controlled clinical neuroprotection trials for AIS have cast doubts as to whether neuroprotection in humans is biologically possible and, given the complexities of human stroke syndromes, whether it is a clinically practicable therapy for patients experiencing AIS in the community. The questions of feasibility and practicability cannot be resolved simultaneously. Feasibility is a question of biology: Whether it is possible to achieve tissue sparing after AIS in the high-order brains of humans? The gloomiest hypothesis is that tissue sparing and preservation of neurological function may be possible in low-order species, such as rats, but not in humans. Under this hypothesis, there might be as-yet-unresolved but fundamental anatomic, genetic, or biological differences between low-order species and humans that preclude neuroprotection in the high-order brain. However, recent studies with postsynaptic density-95 (PSD-95) protein inhibitors, a promising class of neuroprotectant that uncouple PSD-95 from neurotoxic signaling pathways in central neurons,4–7 repudiate this concern. They show that neuroprotection is unequivocally possible not only in the rodent brain, but also in the high-order brain of old-world primates8,9 and in …

Brain Injury: Refinement and Restoration—The Light Is Coming On

The scope and extent of traumatic brain injury (TBI) as a regional, national, and international problem cannot be underestimated. The U.S. Centers for Disease Control and Prevention has estimated that 1.7 million people sustain TBI annually and that 75%-85% of these injuries are mild [1]. Sports and bicycle accidents account for 26% of mild TBI, with approximately 300,000 persons with sports-related TBIs presenting to the emergency department yearly. The vast majority of those were due to concussions. No other health issue has received more media recognition than sports-related concussion. Recent findings describe the high incidence of TBIs among service members returning from conflicts in Iraq and Afghanistan [2]. Yet, for sportsor military-related injuries, little in the way of compelling evidence is available to guide therapy. These numbers are additive to the large number of individuals who experience lifelong disability related to severe TBI each day. Although numerous clinical trials for neuroprotection have failed to show efficacy, a bright light exists in the refinement and neurorestorative arenas for the near future [3].

Urinary Erythropoietin Concentrations after Early Short-Term Infusion of High-Dose Recombinant Epo for Neuroprotection in Preterm Neonates

Background: High-dose recombinant human erythropoietin (rEpo) has first been administered in clinical trials for neuroprotection in very preterm neonates at high risk of brain injury and in (near-) term neonates with hypoxic-ischemic encephalopathy. However, recent trials in adults raised concerns about the safety of high-dose rEpo for neuro- and cardioprotection. Objectives: To evaluate the putative accumulation or renal leakage of Epo as a function of developmental stage after repetitive early short-term infusion of high-dose rEpo (3 × 3,000 U/kg within 42 h after birth; NCT00413946) for neuroprotection in very preterm infants. Methods: Epo concentrations were measured using the ELISA technique in the first two consecutive urine specimens after each rEpo infusion. Results: Renal Epo excretion was significantly higher in preterm infants with gestational ages <29 weeks than in more mature infants and reached up to 23% of the administered rEpo within 8 h after each infusion. The urinary Epo concentration did not increase after three repetitive infusions of high-dose rEpo. The ratio of urinary Epo to total protein concentrations was the same in infants with gestational ages <29 weeks and in those with gestational ages ≥29 weeks. Conclusions: Our data suggest that the higher renal Epo excretion in more immature infants may be attributed to a higher glomerular filtration leakage due to the lower maturation of the kidneys and argue against saturation kinetics after multiple doses of 3,000 U/kg rEpo. This information should be considered in future trials on the use of rEpo for neuroprotection in neonates.

Basal ganglia atrophy in prodromal Huntington's disease is detectable over one year using automated segmentation

Future clinical trials of neuroprotection in prodromal Huntington's (known as preHD) will require sensitive in vivo imaging biomarkers to track disease progression over the shortest period. Since basal ganglia atrophy is the most prominent structural characteristic of Huntington's pathology, systematic assessment of longitudinal subcortical atrophy holds great potential for future biomarker development. We studied 36 preHD and 22 age-matched controls using a novel method to quantify regional change from T(1) -weighted structural images acquired 1 year apart. We assessed cross-sectional volume differences and longitudinal volumetric change in 7 subcortical structures-the accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. At baseline, accumbens, caudate, pallidum, and putamen volumes were reduced in preHD versus controls (all P < .01). Longitudinally, atrophy was greater in preHD than controls in the caudate, pallidum, and putamen (all P < .01). Each structure showed a large between-group effect size, especially the pallidum where Cohen's d was 1.21. Using pallidal atrophy as a biomarker, we estimate that a hypothetical 1-year neuroprotection study would require only 35 preHD per arm to detect a 50% slowing in atrophy and only 138 preHD per arm to detect a 25% slowing in atrophy. The effect sizes calculated for preHD basal ganglia atrophy over 1 year are some of the largest reported to date. Consequently, this translates to strikingly small sample size estimates that will greatly facilitate any future neuroprotection study. This underscores the utility of this automatic image segmentation and longitudinal nonlinear registration method for upcoming studies of preHD and other neurodegenerative disorders.

Clinical Trials for Neuroprotection in ALS

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Brain recovery – towards an unified theory

Brain recovery – towards an unified theory

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Clinical neuroprotection in Parkinson's disease — Still waiting for the breakthrough

Recent research in the pharmacotherapy of Parkinson's disease (PD) has been able to provide numerous agents for the symptomatic control of motor impairments, but has failed to identify substances capable to slow down or even halt the progression of the disease. In the absence of disease-modifying therapies, affected patients develop marked disability within some years after the onset of motor symptoms, which can be alleviated but eventually not prevented with currently available medical and surgical therapies. Despite promising results from preclinical studies, outcomes of clinical neuroprotection trials have been repeatedly disappointing, which calls for a review of our approach to this topic. This article attempts to explain the need for neuroprotective therapies in PD, discusses results and limitations of previous clinical trials and provides some food for thought for the future research of neuroprotection in PD. Previous experiences from neuroprotection studies may have been discouraging, but also teach us some important lessons for the next generation of preclinical and clinical trials. Firstly, our currently used animal models for PD need to be refined in order to more reliably predict the efficacy of putative neuroprotective agents in subsequent clinical studies. Furthermore, changes in the methodology and design of future neuroprotection trials are required in order to exclude an impact of confounding symptomatic effects on observations. Finally, coordination and concentration of future research on the most promising agents will be necessary in order to accelerate the search for neuroprotective therapies in PD. Just as the pathogenesis of the disease is manifold, it may be this multilateral approach that eventually leads us to a breakthrough in finding neuroprotective agents for PD, if they exist.

Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease

During the last 20 years, an enormous research effort and hundreds of millions of dollars have been spent attempting to develop and prove that drugs may slow the rate of progression of Parkinson disease (PD). At the time of writing, no drug has yet satisfied the rigorous criteria set by clinicians and licensing authorities for a neuroprotective agent. Despite this apparent failure, numerous important lessons have been learned, and some areas for optimism have emerged. Dopaminergic drugs have, for 40 years, been the basis for the treatment of the predominant early motor features of PD. Several of these drugs have also demonstrated an ability to protect cells, including neurons, against a range of toxins that are of relevance to the pathogenesis of PD. Some have entered clinical trials for neuroprotection, and a few have produced a positive result according to the endpoint selected. The interpretation of these trials is the subject of some debate. A pattern has emerged in these and other clinical trials, which has lead to a novel concept for neuroprotection, and that is simply to treat early rather than delay. The basis for this may lie in the support of basal ganglia compensatory mechanisms and the restoration of normal dopaminergic transmission.